Comparative persistence and adherence to overactive bladder medications in patients with and without diabetes.

AIMS: This retrospective administrative claims-based study evaluated comparative persistence and adherence to overactive bladder (OAB) medications in US patients with and without diabetes. METHODS: Patients ≥ 18 years who initiated OAB medications between 1 January 2005 and 30 June 2008 were analysed from the Truven Health MarketScan Commercial and Medicare Supplemental databases. A 12-month baseline period prior to OAB medication initiation was used to classify patients into diabetes and non-diabetes cohorts, and measure demographic and clinical characteristics. Patients in each cohort were directly matched 1 : 1 based on index year, age, gender and geographic region. Multiple logistic regression was used to compare cohorts on outcomes of ≥ 80% adherence to OAB medications and refilling a second OAB medication prescription. Cox's proportional hazards model compared time to non-persistence with OAB medications between both cohorts. RESULTS: In total, 36,560 patients were included in each cohort. Compared with the non-diabetes cohort, the diabetes cohort had 21.5% higher odds of ≥ 80% adherence to OAB medications, 16.6% higher odds of filling a second OAB medication prescription and 10.3% lower hazard of non-persistence with OAB medications during a 12-month evaluation period. CONCLUSIONS: Patients with diabetes were more persistent and adherent to OAB medications and had higher odds of filling a second medication prescription than patients without diabetes. Further research is needed to identify factors responsible for these findings.

Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Safety and tolerability of apomorphine SL (Uprima).

The side effect profile of apomorphine SL (2-6 mg) has been determined in clinical studies of over 5000 patients using over 120 000 doses. Apomorphine, 2 and 3 mg, has been shown to have an excellent safety profile. The most commonly occurring side effects (<7%), nausea, headache and dizziness, tend to be mild and not compliance limiting. Neither the incidence nor the nature of the side effects is significantly affected by common co-morbidites or by the use of many concurrent medications. Over this dose range there is little evidence of vasoactivity; there is little change in haemodynamic baseline and there is no synergistic effect with nitrates. Although syncope can occur at higher doses, it is rarely observed at approved doses (<0.2%).

The prevalence of variant alkaline phosphatase in hepatocellular carcinoma in southern African blacks.

The prevalence of variant alkaline phosphatase in the serum of 335 southern African blacks with hepatocellular carcinoma was determined using polyacrylamide gel electrophoresis. The isoenzyme was detected in 2% (seven of 335) of the patients: it could not be found in the serum of 300 matched, healthy individuals or in 56 patients with various benign hepatic diseases. Variant alkaline phosphatase is thus of little use as a diagnostic marker of hepatocellular carcinoma in southern African blacks. The reported prevalence of this isoenzyme in hepatocellular carcinoma ranges between 3% and 31%. Higher frequencies usually are recorded in populations with a low incidence of the tumor, and the lowest frequencies have been found in Chinese patients. Our finding of variant alkaline phosphatase in only 2% of another high incidence population fits this trend. Patients with tumors that secreted the variant isoenzyme had a significantly higher serum total alkaline phosphatase activity than those with tumors lacking this property.

Nucleic acid sequence analysis of the precore region of hepatitis B virus from sera of southern African black adult carriers of the virus.

Our purpose was to ascertain if mutations of the precore region of the hepatitis B virus genome, in particular the 1896 stop codon mutation, are responsible for the 95% hepatitis B e antigen (HBeAg)-negativity rate in southern African black adult carriers. Hepatitis B virus (HBV) DNA was extracted from the serum of 57 asymptomatic carriers (42 HBeAg-negative; 15 HBeAg-positive), the precore region was amplified using the polymerase chain reaction (PCR), and sequenced. Six carriers (14.6%) had mutations known to prevent HBeAg synthesis: 4 involved the precore initiation codon (1814), and one created a stop codon at 1874. The 1896 mutation occurred alone in one carrier only (2.4%). The infrequency of the 1896 mutation can be explained by the high prevalence (70%) of the adw subtype in the carriers studied. Inter alia, adw differs from ayw in that codon 15 is comprised of CCC instead of CCT. The presence of C instead of T in position 1858 precludes the G-to-A mutation at 1896 because the coexistence of these two mutations would destabilize the stem-loop structure of the RNA encapsidation signal, a finding confirmed by our observation that the CCC polymorphism and the 1896 mutation were mutually exclusive. Ten HBeAg-negative carriers (24%) had a missense mutation at position 1862 in the bulge of the RNA encapsidation signal, which may possibly affect HBeAg expression by interfering with either priming of reverse transcription or signal peptide cleavage. We conclude that the 1896 stop codon mutation accounts for a minority only of HBeAg-negative black carriers. A missense mutation in the bulge of the encapsidation signal may contribute to HBeAg negativity.

Comparison of hepatitis B virus DNA extractions from serum by the QIAamp blood kit, GeneReleaser, and the phenol-chloroform method.

The abilities of GeneReleaser and QIAamp to extract the hepatitis B virus (HBV) DNA template from serum for amplification by PCR were evaluated and compared with that of the standard phenol-chloroform method. Differences in the sensitivities of the three methods were revealed by nested PCR of HBV DNA extracted from serially diluted hepatitis B e antigen (HBeAg)-positive (high-titer) serum. Phenol-chloroform was found to be the most sensitive extraction method but was time-consuming and labor intensive, and the many steps required increased the possibility of contamination. In a titration of HBeAg-negative (low-titer) serum, all three methods coupled with nested PCR were capable of detecting low levels of HBV DNA. In the case of QIAamp and GeneReleaser, the extraction was relatively simple and rapid. The higher quantity of serum (200 microliters) used in the QIAamp extraction did not provide higher sensitivity, possibly because of incomplete removal of Taq polymerase inhibitors from the serum or inadequate disruption of the virion. GeneReleaser was more efficient because it gave the same detection limit in low-titer serum as phenol-chloroform even though it utilizes only 5 microliters of serum. However, it did not produce consistent amplifications of HBV DNA, giving false-negative results in 7 of the 50 cases (14%) in one experiment. Use of a larger volume of serum and replicate extractions may overcome this problem. Advantages thus exist in each of the extraction methods, and these should be weighed against the disadvantages when deciding which extraction method is appropriate.

Hepatitis B virus precore mutants in serum and liver of Southern African Blacks with hepatocellular carcinoma.

BACKGROUND/AIM: The aim of this study was to sequence the precore region of HBV isolated from serum and tumorous and non-tumorous liver tissue from patients with hepatocellular carcinoma to identify mutations that might play a role in malignant transformation. METHODS: HBV DNA was extracted from 62 sera, 14 tumorous and 12 non-tumorous liver tissue samples of patients with hepatocellular carcinoma, amplified by the polymerase chain reaction and sequenced directly. RESULTS: Thirty-nine patients were HBeAg-negative and 23 HBeAg-positive. Missense mutations were present predominantly in HBeAg-negative sera. The most common missense mutation, a guanine to thymine transversion, occurred at nucleotide 1862 in the bulge of the encapsidation signal; it was more prevalent in HBeAg-negative (10/39) than in HBeAg-positive patients (1/23) (p = 0.03). Mutations known to prevent HBeAg synthesis were detected in seven sera; five with an 1896 stop-codon mutation, one with an 1817 nonsense mutation, and one with a frameshift mutation caused by an insertion between 1838 and 1839. Missense mutations and deletions were present more often in tumorous tissue derived from HBsAg-negative patients. In the tumours missense mutations occurred at position 1862 and 1899, and the deletions affected direct repeat 1 and/or the encapsidation signal and included the x gene stop-codon. CONCLUSIONS: The 1862 mutation, and other missense mutations and deletions detected in the precore gene, may disrupt HBV DNA replication and/or signal peptide cleavage leading to HBeAg-negativity. Disruption of viral replication may promote integration of unencapsidated replicative intermediates and hence contribute to hepatocarcinogenesis.

Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction.

OBJECTIVE: To establish the efficacy and safety of a fixed, 3-mg dose of apomorphine SL compared with placebo, and to compare 3 mg with 4 mg apomorphine SL in patients with erectile dysfunction. METHODS: This randomized, double-blind, crossover study included 296 heterosexual men with ED of various etiologies and severities. Two crossover groups were evaluated separately: 3 mg apomorphine SL vs. placebo (n = 194), and 3 vs. 4 mg apomorphine SL (n = 102). The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse; additional variables included the percentage of attempts resulting in intercourse and time to erection. Partner assessments were also analyzed. RESULTS: 3 mg apomorphine SL was significantly more effective than placebo (p<0.001) for the percentage of attempts resulting in erections firm enough for intercourse and resulting in intercourse, as assessed by both patients and partners. Median time to erection was 18.8 min. The 3-mg dose was not significantly different from 4 mg in the evaluation of efficacy variables, but the incidence of adverse events was higher with 4 mg. Nausea was the most common event, reported by 3.3% of patients on 3 mg vs. 14.1% on 4 mg; in the placebo comparison, nausea was reported by 7.0% of patients taking 3 mg apomorphine SL vs. 1.1% of those taking placebo. CONCLUSIONS: 3 mg apomorphine SL was significantly more effective than placebo and comparable to 4 mg, while offering an improved risk-benefit ratio.

The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in Southern African blacks.

Membranous obstruction of the inferior vena cava has been incriminated as a risk factor for hepatocellular carcinoma in South African Blacks and in Japanese. However, the frequency with which this anomaly is found in patients with hepatocellular carcinoma, and hence its numerical importance as an etiological association of the tumor, has not been ascertained. Using radionuclide and contrast venography as well as necropsy and laparotomy examination, we investigated 162 unselected southern African Blacks with hepatocellular carcinoma together with appropriate controls for the presence of membranous obstruction of the inferior vena cava. Membranous obstruction of the inferior vena cava was detected in six of 162 (3.7%) hepatocellular carcinoma patients, compared with one of 279 subjects (0.36% p = 0.011) dying a violent death, none of 55 patients (p = 0.169) with malignant disease other than hepatocellular carcinoma and eight of 150 patients (5.3%; p = 0.336) being investigated for conditions which might have been associated with membranous obstruction of the inferior vena cava. Six of the 15 individuals (40%) found to have membranous obstruction of the inferior vena cava had concomitant hepatocellular carcinoma, confirming that membranous obstruction of the inferior vena cava constitutes a risk factor for the development of the tumor. However, only a very small proportion of hepatocellular carcinoma patients have this abnormality, so that it is a minor causal association of the tumor only.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-L-fucosidase as a serum marker of hepatocellular carcinoma in southern African blacks.

The purpose of this study was to compare alpha-L-fucosidase and alpha-fetoprotein as serum markers of hepatocellular carcinoma in 72 southern African blacks with this tumour and 64 matched patients with benign hepatic diseases which might be mistaken clinically for hepatocellular carcinoma. Alpha-L-fucosidase activity was assayed using p-nitrophenyl-L-fucopyranoside (pNpf) as a substrate and alpha-fetoprotein concentrations were measured by radioimmunoassay. Serum alpha-L-fucosidase activity in the patients with hepatocellular carcinoma (mean 1,268, s.e.m. +/- 83.7, median 1,150 and range 38-3,698 nmol pNpf ml-1 h-1) was significantly higher than that in the matched controls (mean 798, s.e.m. +/- 65.8, median 648 and range 273-3,825 nmol pNpf ml-1 h-1) (P = 0.0001). However, alpha-L-fucosidase was both less sensitive (75 versus 87%) and less specific (70 versus 87%) than alpha-fetoprotein as a serum marker of hepatocellular carcinoma. When, in an endeavour to eliminate false-positive results, the diagnostic cut-off level for alpha-L-fucosidase was increased to 1,500 nmol pNpf ml-1 h-1 and for alpha-fetoprotein to 400 ng ml-1, the sensitivity of alpha-L-fucosidase fell to 21% whereas that of alpha-fetoprotein remained satisfactory at 78%. If the two markers were used together, the number of false-negative alpha-fetoprotein results was reduced from 13 to 5.5%. We conclude that alpha-L-fucosidase is less useful than alpha-fetoprotein as a single marker of hepatocellular carcinoma in southern African blacks. However, the two markers can profitably be used together.

Differential lectin reactivities of alpha-fetoprotein in hepatocellular carcinoma: diagnostic value when serum alpha-fetoprotein levels are slightly raised.

The specificity and sensitivity of alpha-fetoprotein (AFP) binding to Concanavalin-A (Con-A) and Lens culinaris agglutinin (LCA) in 26 South African blacks with advanced symptomatic hepatocellular carcinoma (HCC) but only slightly raised serum AFP concentrations (20-500 ng/mL) was compared with that in patients with similar serum AFP levels from diseases that might be mistaken clinically for HCC (seven 'benign' liver disease [BLD] patients and six with metastatic liver disease [MLD] from gastrointestinal tumours). Con-A-Sepharose-4B affinity chromatography did not differentiate between the different groups: fucosylation rations for the HCC patients were 0.81 +/- 0.60, compared with 0.63 +/- 0.27 and 0.54 +/- 0.32 in patients with BLD and MLD, respectively. Electrophoresis of AFP serum and fraction in the presence or absence of Con-A and LCA showed an increase in the AFP C2 band. Rank correlation analysis of the AFP L2 and L3 bands combined could distinguish between patients with HCC and other hepatic diseases (P less than 0.05).

A European multicentre study to evaluate the tolerability of apomorphine sublingual administered in a forced dose-escalation regimen in patients with erectile dysfunction.

OBJECTIVE: To determine the risk-benefit ratio of a forced dose-escalation regimen (2 to 3 to 4 mg) in a European clinical study evaluating apomorphine sublingual (SL) in treating erectile dysfunction (ED), by evaluating the overall tolerability and efficacy of the regimen compared with placebo in patients with ED, and evaluating efficacy by assessing the proportion of successful attempts resulting in sexual intercourse. PATIENTS AND METHODS: This randomized, double-blind, two-arm, parallel-group study was conducted in 507 patients enrolled at 34 European sites. After a 1-2 week screening period, patients were treated for 8 weeks with either placebo or apomorphine SL administered as a forced dose-escalation regimen. Heterosexual men (aged 18-70 years) were eligible for participation in the study if they were in stable health, a stable relationship of > or = 6 months duration, had a history of erectile inability, and were diagnosed with ED (successful in fewer than half of attempts to attain and maintain an erection firm enough for intercourse during the 30 days before screening). Patients provided information (recorded on diary cards and reviewed at each study visit) about the frequency and success in achieving erections and of sexual intercourse attempts during both the screening and treatment periods. The dosing regimen required patients to take one tablet of apomorphine SL (2 mg for 2 weeks, then 3 mg for 2 weeks and finally 4 mg for the remaining 4 weeks) or placebo 15-25 min before intercourse, and intercourse was to be attempted at least twice a week. Safety data were collected throughout the 8-week study period, and included recording adverse events, vital signs and changes in laboratory test values for standard haematology and biochemistry variables. The primary efficacy variable was the proportion of successful attempts, defined as an erection rigid enough for sexual intercourse, occurring after dosing (successful intercourse rate). The proportion of erections achieved was a secondary efficacy variable. RESULTS: Of the 507 patients, 254 received apomorphine SL and 253 received placebo; 87% of patients in both groups completed the 8-week treatment period. Of the patients receiving apomorphine SL, 24% had hypertension, 11% had coronary artery disease, 10% had diabetes, and 5.5% had benign prostatic hypertrophy; 62.6% of treated patients received concomitant medications for these maladies. The treatment groups were balanced for demographic and baseline variables, including comorbidity factors. Treatment-emergent adverse events, reported by > 5% of patients in the treated group, were nausea (9.8%), dizziness (7.1%) and headache (6.7%), compared with 0.4%, 2.4% and 4.0%, respectively, in the placebo group. Sixty-six patients withdrew from the study, 16 because of study drug-related adverse events (12 from the apomorphine and four from the placebo group). Six patients (three in each group) reported a total of nine serious treatment-emergent adverse events, all of which resolved by the end of the study. In the intention-to-treat population, the proportion of successful attempts at sexual intercourse and of erections were statistically greater in the apomorphine than in the placebo group (P = 0.001 and 0.021, respectively); analysis of the per-protocol population results confirmed this significant difference. CONCLUSION: This European study supports the safety and tolerability of apomorphine SL despite the forced escalation to a 4-mg dose (exceeding the approved 2-3 mg dose). Adverse effects were not treatment-limiting. These results further support the clinically significant efficacy of apomorphine SL for treating ED at all doses used. The risk/benefit ratio supports apomorphine SL as a safe and effective alternative in managing ED.

Clinical and molecular features of the hereditary mixed polyposis syndrome.

BACKGROUND & AIMS: Various inherited syndromes predispose to the development of colonic juvenile polyps and colorectal cancer, with potential importance for sporadic tumorigenesis. This study describes features of a possibly new syndrome of atypical juvenile polyps and other colonic tumors and compares these features with those of known gastrointestinal tumor syndromes. METHODS: A large family, St. Mark's family 96, with a tendency to develop colonic polyps of mixed histological types is described. Genetic linkage to known polyposis syndromes has been tested. RESULTS: Adenomatous and hyperplastic polyps occur in affected members of the family, although the characteristic lesion is an atypical juvenile polyp. Some affected individuals have developed polyps of more than one type, and individual polyps may contain features of more than one histological type. Polyps can undergo malignant change. Typically, fewer than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of polyps. The family's polyps seem to be inherited in an autosomal-dominant fashion, but the disease is probably unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, hMSH2, and hMLH1. CONCLUSIONS: We term this family's disease hereditary mixed polyposis syndrome (HMPS). Although mutations in the putative HMPS gene may be responsible for syndromes such as juvenile and Peutz-Jeghers polyposes, HMPS may also be a distinct disease.