A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Clinical significance of SNAP somnography test acoustic recording.

OBJECTIVE: To examine the clinical significance of acoustic data recorded by the SNAP home polysomnography system (SNAP Laboratories, Glenview, IL). STUDY DESIGN AND SETTING: Retrospective analysis of SNAP data from 59 patients undergoing evaluation for sleep apnea at the University of Nebraska Medical Center and an associated private practice in Omaha, NE. RESULTS: Snoring did not correlate with anthropometric variables such as body mass index and neck circumference. Statistical analysis showed no correlation between respiratory disturbance index and the maximum or average loudness of snoring. Average loudness was predictive of the presence of sleep apnea. Spectral analysis of snoring sonography found that the proportion of snoring events associated with a palatal source correlated strongly with the loudness of snoring. CONCLUSION: These data suggest that analysis of snoring has limited utility in the evaluation of the patient with sleep apnea but may be able to select patients who would benefit from palatal procedures to reduce snoring.     

A disorder of lightness discrimination in a case of visual form agnosia

Benson and Greenberg (1969) described an "agnosic" patient whose severe visual recognition disorder could be accounted for in terms of a deficit in the perception of shape. We report here on a recent case of this disorder (visual form agnosia), and have found that she performs very poorly on tasks of discriminating shades of grey, although she is able to discriminate between hues. This sensory deficit helps to explain some of her perceptual difficulties; it also provides further evidence for parallel feature-processing in the human brain complementary to and consistent with recent physiological data on the visual cortex in animals.     

Glucose tolerance in Papua New Guinea: ethnic differences, association with environmental and behavioural factors and the possible emergence of glucose intolerance in a highland community

That Melanesians of non-Austronesian genetic ancestry may be relatively resistant to glucose intolerance was supported by the results of a study of two semitraditional non-Austronesian villages in the Papua New Guinean highlands in 1983, in which an absence of diabetes and a high degree of glucose tolerance and insulin sensitivity were observed. The second of this series of surveys was conducted in 1985 in three non-traditional communities: a periurban, non-Austronesian village in the highlands, and rural and periurban Austronesian villages in coastal locations. Although an absence of diabetes was demonstrated once again in the highlanders, these periurban subjects showed an unexpectedly high insulin response which may be a precursor of glucose intolerance. The notion that highland communities that are living in non-traditional circumstances in Papua New Guinea presently are in "metabolic transition" towards diabetes and other non-communicable diseases, if correct, is of importance to the public health of the nation. In the periurban, coastal-dwelling Austronesians, diabetes with severe hyperglycaemia was demonstrated, and there was some evidence of a secular trend towards increasing glucose intolerance. The two-hour plasma glucose concentrations were shown to be associated with obesity, modernity and Seventh-Day Adventist religious persuasion. However, important and unexplained differences in glucose tolerance remained between rural and periurban coastal dwellers after taking these factors into account.     

Age-related variations in renal structure and function in Sprague-Dawley rats

Data from 500 male and 500 female Sprague-Dawley rats used as controls in studies performed at Huntingdon Research Centre to assess the safety of drugs were sampled at 17, 30, 56, 82, or 108 weeks of age. Plasma urea nitrogen levels remained constant, except in aged males. Aging caused increased proteinuria and decreased urinary concentrating ability, in addition to increased size, weight, and degree of cortical scarring of kidneys. Chronic progressive nephropathy, first seen histopathologically at 30 weeks of age, accounted for these changes and ultimately affected 81% of male and 44% of female rats. One-fifth of two-year-old male rats had diffuse parenchymal damage and a small number also had secondary hyperparathyroidism. Other notable changes included basophilic (often colloid-filled) cortical tubules, mononuclear cell infiltrations, parenchymal and pelvic mineralization, urothelial hyperplasia, and pyelonephritis. Miscellaneous low incidence findings included one lipomatous tumour and generalized lymphosarcoma.     

Stage, survival and delays in lung, colorectal, prostate and ovarian cancer: comparison between diagnostic routes

BACKGROUND: Very few studies have reported cancer outcomes of patients referred through different routes, despite the prominence of current UK cancer urgent referral guidance. AIM: This study aimed to compare outcomes of cancer patients referred through the urgent referral guidance with those who were not, with respect to stage at diagnosis, survival, and delays in diagnosis. Design of study: Analysis of hospital records. SETTING: One hospital trust in England. METHOD: The records of 889 patients diagnosed in 2000-2001 with one of four types of cancer were analysed: 409 with lung cancer; 239 with colorectal cancer; 146 with prostate cancer; and 95 with ovarian cancer. Outcome measures were diagnostic stage, survival, referral and secondary care delays. RESULTS: For lung cancer, urgent referrals had more advanced TNM (tumor, node, metastasis) stage than patients diagnosed through other routes (P = 0.035) and poorer survival (P = 0.020). There was no difference in stage or survival for the other cancers. For each cancer, a higher proportion of urgent referrals was seen within 2 weeks. Secondary care delays for lung and colorectal cancer were shorter for inter-specialty referrals. CONCLUSION: For patients with lung cancer, the guidance appears to be prioritising those in the more advanced stages of disease. This was not the case for the other three cancers. Referral delays were shorter for patients urgently referred, as is the intention of the guidance. The avoidance of delays in outpatient diagnostics probably accounts for shorter secondary care delays for inter-specialty referrals.     

Sensitivity to eye gaze in prosopagnosic patients and monkeys with superior temporal sulcus ablation

Accuracy at perceiving frontal eye gaze was studied in monkeys and human subjects using a forced-choice detection task on paired photographs of a single human face. Monkeys learned the task readily, but after bilateral removal of the banks and floor of the superior temporal sulcus (STS) they failed to perform the task efficiently. This result is consistent with the conclusion, based on recordings from single cells in awake, behaving monkeys [Perret et al., Physiological Aspects of Clinical Neuro-ophthalmology, Chapman & Hall, London, 1988] that this region of the temporal lobe is important for coding information about eye-gaze of a confronting animal. Human subjects were given identical stimuli in a task where they were asked to detect "the face that is looking straight at you". Human performance is sensitive to the degree of angular deviation from the frontal gaze position, being poorest at small angular deviations from 0 degrees. This was also true of monkeys viewing these stimuli, pre- and post-operatively. Compared with normal controls, two humans prosopagnosics were impaired at this task. However the extent of impairment was different in the two patients. These findings are related to earlier reports (including those for patients with right-hemisphere damage without prosopagnosia), to normal performance with upright and inverted face photographs, and to notions of independent subsystems in face processing.     

Effects of temporal cueing on residual visual discrimination in blindsight

We tested the ability of a blindsight patient, GY, to identify in which of two locations a target was presented in a spatial two-alternative forced choice paradigm (spatial 2AFC). On each trial the subject was asked to make a second manual response indicating whether he had had any awareness of an event occurring during the trial. A cue, presented at the fixation location, could signal the 0.4 s period over which the target appeared within the 10 s duration of each trial. Targets of three contrasts, 93, 43 and 22% were used. We found that GY's ability to discriminate the location of targets in his blind field remained significantly above chance, with and without cueing, for each contrast. Cueing, did, however, significantly improve his performance for low contrast targets. When he performed a similar task with near threshold contrast targets in his spared visual field his discrimination was at chance unless the presentation of targets was cued, despite his reporting more awareness for these stimuli than he did for low-contrast stimuli in his blind field. These results are compared with those previously reported in monkeys who received lesions to their visual cortices as infants or adults. We conclude that (1) GY's blindsight is qualitatively different from near-threshold normal vision. (2) In common with infant-lesioned monkeys his blindsight remains even in the absence of temporal cues. (3) Residual vision is subject to modulation by attentional processes, or arousal, associated with temporal cueing.