Differences in bioavailability between 60 mg of nifedipine osmotic push-pull systems after fasted and fed administration.

OBJECTIVES: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. MATERIALS AND METHODS: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 - 44 years), mean weight of 79.7 kg (range 66.0 - 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m(2) (range 22.1 - 26.9 kg/m(2)). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. RESULTS: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC(0-tlast)- and C(max)-values, respectively were 466.7 h*ng/ml (AUC(0-tlast)) and 21.9 ng/ml (C(max)) for Test and 507.8 h*ng/ml (AUC(0-tlast)) and 22.0 ng/ml (C(max)) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 - 105.5% for AUC(0-tlast), as well as 99.8% and 88.6 - 112.4% for C(max). Larger differences were found for AUC(0-9h) (PE: 54.8%; CI: 45.8 - 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC(0-tlast) and C(max), were considerably lower (differences also statistically significant) after administration of Test with 481.8 h*ng/ml for AUC(0-tlast) and 25.3 ng/ml for C(max) in comparison to Reference tablets with 595.9 h*ng/ml for AUC(0-tlast) and 31.9 ng/ml for C(max). Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 - 88.5% for AUC(0-tlast), as well as 79.6% and 70.3 - 90.0% for C(max). Differences were also even more expressed for AUC(0-9h) (PE: 54.9%; CI: 47.4 - 63.5%) determined as parameter for early exposure. CONCLUSION: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment.

Familial adenomatous polyposis: a case report and review of the literature.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by diffuse intestinal polyposis, specific gene mutation, and predisposition for developing colon cancer. Left untreated, patients with FAP will develop colorectal carcinoma during early adulthood. Hence, early detection and surgical intervention are of the utmost importance. Colectomy is required and may include an ileal pouch with ileoanal anastomosis, which eliminates the colon and rectal disease while preserving fecal continence and avoidance of a permanent ileostomy. Advances in the treatment of FAP with associated reduction in mortality from colorectal carcinoma make extracolonic manifestations of the disease more common and life-long surveillance is mandatory. The most life-threatening extracolonic manifestations of FAP are periampullary carcinoma and desmoid tumors. The upper gastrointestinal tract should be monitored endoscopically at the time of diagnosis and assessed regularly thereafter. Duodenal adenomas should be resected so as to avoid the devastating effects of invasive periampullary carcinoma. Additionally, the development of desmoid tumors needs to be monitored (by CT or MRI), so as to avoid the severe complications of local invasion. Further research is indicated in the development of effective screening and treatment for this condition.

Motiveless firesetting: implicating partial limbic seizure kindling by revived memories of fires in "Limbic Psychotic Trigger Reaction".

23 unselected juvenile firesetters (M age 12.0 yr.) consisted of seven with schizophrenia, three with organic mental disorder, six with posttraumatic stress disorder, two with severe mental retardation, and two with conduct disorders. Three previously nondestructive boys (M age 11.0 yr.), all of them loners, did not fit such traditional diagnoses. Their fleeting (c. 20 min.) symptoms included flat affect, autonomic arousal, and delusions or hallucinations. It appeared that their motiveless, unplanned acts were each preceded by a chance encounter with an individualized stimulus which revived the three boys' repeatedly ruminated memories of intermittently experienced merely moderate stresses associated with fire, smoke, or matches. Such a sequence of events is characteristic of seizure kindling. One boy's abnormal EEG was congruent with seizures in the temporal lobe area, which includes the amygdala, i.e., that part of the limbic system particularly susceptible to seizure kindling. The three boys' consistent symptomatology was very similar to that reported for 17 men with bizarre homicidal acts implicating a kindled partial seizure called "Limbic Psychotic Trigger Reaction." In primates, too, similar partial nonconvulsive "behavioral seizures" with psychosis-like symptoms can be elicited through experiential kindling.

Heat resistance of Alicyclobacillus acidoterrestris spores as affected by various pH values and organic acids.

Alicyclobacillus acidoterrestris, a thermoacidophilic sporeformer, has caused spoilage of fruit juices which had been treated with thermal processes intended to commercially sterilize the juice. The objective of this research was to document the effect of pH, acid, and temperature on the heat resistance of spores of three fruit-juice isolates of A. acidoterrestris. The thermal resistance of spores of A. acidoterrestris strains VF, WAC, and IP were studied in a model fruit-juice system composed of 12% glucose and 30 mM of either citric, malic, or tartaric acid, adjusted to selected pH values ranging from 2.8 to 4.0. Decimal reduction times (D values) and inactivation rates were determined. Spores of strains VF and WAC were similarly resistant to heat under acidic conditions, while strain IP spores were less resistant. In the range of pH 2.8 to 4.0, a statistically effect of hydrogen ion concentration on heat resistance was observed at lower temperatures, but not at the higher temperatures, but not at the higher temperatures. For examples, at 91 degrees C and pH 3.1 and 3.7, D values were 31.3 and 54.3 min, respectively, while at 97 degrees C D values at pH 3.1 and 3.7 were 7.9 and 8.8 min, respectively. The type of acid did not significantly affect the heat resistance. The zd values ranged from 5.9 to 10 degrees C, depending on the acid, pH, and the strain. The models generated from this research can be used to determine adequate thermal processes, accounting for the acid type, pH, and temperature, to destroy A. acidoterrestris spores in beverages, since this organism is able to survive the typical hot-fill and hold process (2 min at 88 to 96 degrees C) currently used to process fruit juice.

Spatial representation in face drawing and block design by nine groups from hunter-gatherers to literates.

A rank-order correlation was performed for nine cultural groups ranging from preliterate hunter-gatherers to literate medium-city dwellers. Two spatial tests of intrapattern spatial relations were used, the Draw-A-Person-With-Fade-In-Front test and the Kohs Block Design, a test of constructive praxia. In contrast to traditional "Western" evaluations, credit was given for the preservation of the essential intrapattern shapes even when exact spatial relations among these shapes was incorrect. Such "errors" were labelled "neolithic face" patterns and "nonrandom errors," respectively. Analysis suggested that the neglected intrapattern (in contrast to interobject) spatial relational skills emerge with literacy but is not yet actualized in preliterates whose survival requires quick fight or flight response upon prompt, albeit gross, assessment of salient shapes of prey or predators (human or animals). The positive Spearman rank-order correlation of absent or low literacy skills with the percent of "neolithic face" drawings was .95 and with the "nonrandom" block designs .67. Suggestions were developed for assessing certain unusual "ecological" present situations or certain brain dysfunctions.

Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB).

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance-seeking behaviors (ethanol, drugs, tobacco, and food) and other related behaviors (pathological gambling, Tourette's disorder, attention-deficit/hyperactivity disorder). This is the first study supporting a strong association between the dopamine D2 receptor Taq A1 allele with schizoid/avoidant behavior (SAB). Additionally, an albeit weaker association between the 480-bp VNTR 10/10 allele of the dopamine transporter (DAT1) gene with SAB was similarly found.

Forensic significance of the limbic psychotic trigger reaction.

During the "decade of the brain," competent expert testimony should encompass widely neglected, even novel, neurophysiologically plausible explanations for otherwise unexplainable acts. In the case presented here, a sudden, out-of-character, motiveless, unplanned homicidal attack was committed by a patient who demonstrated flat affect, preserved consciousness, and memory of the episode. Transient autonomic hyperactivation and psychosis were suddenly experienced when the victim happened to move his mouth while eating. Following a sudden memory revival of repetitive but moderate bodily stresses, the patient suffered visceral hallucinations of his entire body being cut into pieces with the delusional belief that he was about to be "cannibalized." The patient's sudden and very transient symptomatology is characteristic of 13 interrelated symptoms and signs (including autonomic, e.g., visceral, hyperactivation and psychosis) proposed as a new subtype of a partial seizure, called "limbic psychotic trigger reaction," which has been consistently delineated thus far in 18 white social loners (14 homicidal men, 3 fire setters, and 1 bank robber), who ruminated about past, moderately painful, but repeated events. This rendered them liable to seizure kindling, particularly of the limbic system. Apparently a post-ictal transient frontal lobe deficiency is secondary to the limbic storm. The forensic impact of seizures on cognition (appreciation of the quality of the act) and on volition is discussed.

In similarity judgments hunter-gatherers prefer shapes over spatial relations in contrast to literate groups.

Reverse strategies are used in judgments of similarity by hunter-gatherers who prefer using shapes (attributes) in patterns, and literates who prefer judging relations among shapes. The Kohs Block Design Test was given to healthy hunter-gatherers, 19 stone-age, preliterate, Amazonian Auca Indians and 130 semi-literate Dani and Asmat of inland Indonesian Western New Guinea. Further, 196 literate Indonesian city dwellers served as controls. The Auca and the Dani and Asmat groups preferentially constructed 20 specific, "nonrandom" modifications similar to the Kohs Block Design Test and preserved the salient component shapes but neglected relations among them. Hunter-gatherers' survival depends on prompt assessment of the salient shapes of prey and attackers. By contrast, literacy skills require painstaking assessment of subtle intrapattern spatial relations among shapes.

Retroductive reasoning in a proposed subtype of partial seizures, evoked by limbic "kindling".

This analysis provides a specific example of the generally applicable process of creative delineation of a novel pattern while searching for an explanatory hypothesis for puzzling observations. In so doing, the neglected retroductive form of inference or abduction was used. Central to such a process is the delineation of a specific "generative mechanism" capable of uniting and explaining heretofore unexplained phenomena. Herein the neurophysiologically known mechanism of limbic seizure "kindling" is offered as a unifying explanation for a dozen bizarre phenomena, proposed as a new subtype of partial seizures, "Limbic Psychotic Trigger Reaction." This new syndrome has been proposed over 15 years in 17 male social loners. Upon encounter with an individualized stimulus, which revived in memory prior moderately hurtful experiences, these men suddenly committed motiveless, unplanned acts with flat affect, transient psychosis and autonomic arousal, showing no quantitative impairment of consciousness and so without memory loss for their perplexing homicidal acts (13 cases), firesetting (3 cases), or bank robbery (1 case). Events occurred in three phases reminiscent of seizures: (1) aura-like puzzlement, (2) transient ictus with a limbic release of predatory or defensive aggression (circa 20 min.), and (3) postictal inefficient actions, implicating a transient frontal lobe system dysfunction secondary to the limbic hyperactivation. The 17 men were of diverse backgrounds, but all without history of prior violence or severe emotional trauma. Seven of 17 had some abnormal tests at some time during their lives and eight known histories of typically overlooked closed-brain injury. Brain damage may facilitate seizure "kindling" but has been traditionally observed in mammals and in a few humans without such damage.

Neuropsychiatric update of the crime "profile" and "signature" in single or serial homicides: rule out limbic psychotic trigger reaction.

A neuropsychiatric and -psychological update of the crime "profile" and "signature" is a necessary addition to the traditional sociopsychological model likely to miss limbic system dysfunctioning. Thus, occurrence of a brief (c. 20 minutes) limbic seizure has been proposed based on behaviors of 12 white male homicidal loners, who showed a dozen symptoms and signs: Limbic Psychotic Trigger Reaction. Readily overlooked can be (a) a transient psychosis (hallucinations and/or delusions), (b) autonomic hyperactivation (e.g., loss of bladder control, nausea, ejaculation), (c) motiveless, out-of-character, unplanned, and well-remembered homicidal acts, (d) committed with a flat affect (not emotionally or impulsively provoked), (e) typically involving a stranger who happened to provide an objectively harmless and only subjectively important stimulus. (f) Such an individualized stimulus triggered the memory revival of mild to moderate but repeatedly experienced hurts. Such a specific sequence of events implicates the specific mechanism of limbic seizure, "kindling," which does not necessarily involve motor convulsions. Repetition of such limbic episodes with "criminal acts" is conceivable under specific circumstances including cases in which the triggering stimulus is associated with pleasurable delusions (e.g., of grandiose power or wealth) or constitutes a specific aspect of a basic drive motive. For example, eating or sexual activities might be planned but degenerate into a limbic episode with a specific core symptomatology.

Overwhelming remembrance of things past: Proust portrays limbic kindling by external stimulus--literary genius can presage neurobiological patterns of puzzling behavior.

Proust detailed inexplicable behavior long before the neurobiologists Goddard and McIntyre in 1972 demonstrated that intermittent repetition of harmless stimuli can cause "kindling" of a seizure (with or without motor convulsions). Such brief seizures can occur especially in the evolutionarily old limbic system which mediates basic drives, their concomitant emotions, and certain aspects of memory. It appears that in humans the influence of specific external stimuli that revive the memory of repeated past experiences may "kindle" a transient episode of limbic overactivation. Thereupon the normal balance between the limbic and frontal lobe systems is disturbed (for a few minutes) as are normal human decision making and control of action. Linked with such a transient frontolimbic imbalance is out-of-character behavior, psychosis (hallucinations or delusions), autonomic activation, and severe distortion of affect and of action, culminating in extreme cases in a "Limbic Psychotic Trigger Reaction," as proposed by Pontius in 1981, in motiveless homicidal acts with mostly preserved consciousness and memory for the acts.

Neuroethics vs neurophysiologically and neuropsychologically uninformed influences in child-rearing, education, emerging hunter-gatherers, and artificial intelligence models of the brain.

Potentially negative long-term consequences in four areas are emphasized, if specific neuromaturational, neurophysiological, and neuropsychological facts within a neurodevelopmental and ecological context are neglected in normal functional levels of child development and maturational lag of the frontal lobe system in "Attention Deficit Disorder," in education (reading/writing and arithmetic), in assessment of cognitive functioning in hunter-gatherer populations, specifically modified in the service of their survival, and in constructing computer models of the brain, neglecting consciousness and intentionality as criticized recently by Searle.

Infanticide in Limbic (?) Psychotic Trigger Reaction in a man with jacksonian and petit mal (?) seizures: "kindling" by traumatic experiences.

A tenth case (a subtype of complex partial seizures) is proposed as a Limbic (?) Psychotic Trigger Reaction. Upon crying, an infant girl was hit fatally by her devoted father while he was off anticonvulsants prescribed for Jacksonian and petit mal (?) seizures with "porencephalic cyst involving motor cortex and limbic system." Crying revived traumatic memories of frequently repeated ("kindling") experiences of his mother crying when hit by his father, in turn sometimes hit by patient while helping the mother. Hitting also had been helpful (cognitive mismatch between helpful and harmful hitting) during the victim's accidental choking 11 days earlier. This had occurred on the same day his distant mother died. Two days later he attempted suicide with anticonvulsants. Symptoms of the well remembered, unmotivated infanticide included flat affect, olfactory and command hallucinations, and delusions of grandeur (his mother leaving him millions and power).

Subtypes of limbic system dysfunction evoking homicide in limbic (?) Psychotic trigger reaction and temporal lobe epilepsy--evolutionary constraints.

Within an evolutionary context two subtypes of limbic system dysfunctioning are compared: (1) the previously proposed limbic psychotic trigger reaction, in which nondrive motivated homicide is triggered by a specific individualized external stimulus, which evokes a brief-lasting active reliving of past (moderately) stressful, frequently repeated ("kindled"?) situations. The brief-lasting out-of-character homicidal episode with flat affect is typically associated with first-time formed or unformed hallucinations of various modalities and with overactivation of the autonomic nervous system. There is no (noticeable) loss of consciousness, enabling the patient's full recall (at times with suicidal attempts) (Pontius, 1981, 1984, 1987). (2) A rare case of homicide during a fugue state with echopraxia in temporal lobe epilepsy is discussed.

Color and spatial error in block design in stone-age Auca Indians: ecological underuse of occipital-parietal system in men and of frontal lobes in women.

The entire healthy adult population of 19 nonmissionized nomadic Auca Indians of the Ecuadorian Amazon basin were given tests involving the four-colored Kohs Block Design, spatial-relational, lexical, and body and face shapes. The test results reveal a specific grouping of deficiencies in color naming (with preservation of color concept), block design especially related to representation, and construction of certain intrapattern spatial relations and graphic representational skills. This ecologically determined grouping of deficiencies suggests a homology to certain neuropsychological syndromes (E. Stengel, 1948, Journal of Mental Science, 94, 46-58; J. de Ajuriaguerra & H. Hécaen, 1960, Le cortex cérébrale; N. Geschwind & M. Fusillo, 1966, Archives of Neurology, 15, 137-146). Further, specifically deficient components of constructional praxis (A. R. Luria & L. S. Tsvetkova, 1964, Neuropsychologia, 2, 95-107) are proposed to reflect gender-related limitations of daily tasks, suggesting occipital-parietal underuse in Auca men and frontal system underuse in Auca women.

Stone-age art "Venuses" as heuristic clues for types of obesity: contribution to "iconodiagnosis".

Two types of obesity (gluteal and abdominal) depicted quite consistently in prehistoric art of different European locations suggests the potential cross-fertilization for physiological inquiry by medical interpretation of prehistoric art, called iconodiagnosis.