Metabolism and excretion of asenapine in healthy male subjects.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

Modes, benefits, and risks of voluntary an delectrically induced exercise in persons with spinal cord injury.

BACKGROUND: Sedentary lifestyles and physical deconditioning are commonly reported among persons with spinal cord injury (SCI), although many forms of exercise have been shown to be beneficial. For individuals unable to perform voluntary exercise, involuntary exercise by electrically stimulated contractions has been used to train individual body segments, invoke cycling movements with or without arm propulsion, and stimulate ambulation. OBJECTIVE: To evaluate the benefits and risks associated with various modes of exercise in persons with SCI. METHODS: Literature review. FINDINGS: Electrical stimulation of local muscle sites increases muscle mass and circulation and favorably alters muscle fiber composition. Electrically stimulated cycling has been observed to improve fitness, lower-extremity circulation, and circulatory response to ischemia and to reverse cardiac muscle atrophy in persons with tetraplegia. Electrically stimulated ambulation improves upper-extremity endurance, lower-extremity circulation, and perception of body image. Studies of arm and wheelchair ergometry show increased arm endurance and decreased cardiovascular risks associated with hyperlipidemia, while resistance training of the upper extremities improves strength and endurance. Because autonomic hyperreflexia, orthostatic intolerance, thermal dysregulation, and fracture are associated with exercise in SCI, risk reduction strategies and prompt intervention are required. CONCLUSIONS: Well-designed programs of exercise are beneficial for persons with tetraplegia and paraplegia. Risks and benefits vary with level of injury. Programs need to address prevention of and intervention for potential adverse effects associated with exercise in individuals with spinal cord dysfunction.

Circuit resistance training improves the atherogenic lipid profiles of persons with chronic paraplegia.

BACKGROUND: People with chronic paraplegia frequently experience dyslipidemias characterized by depressed levels of high-density lipoprotein cholesterol (HDL-C) and elevated levels of low-density lipoprotein cholesterol (LDL-C). These abnormal lipid profiles and poor fitness levels increase their risk for cardiovascular disease. METHODS: To test the hypothesis that circuit resistance exercise training improves both upper-extremity fitness and the atherogenic lipid profile in persons with chronic paraplegia, a homogeneous cohort of 5 men with neurologically complete spinal cord injuries at T6 to L1 underwent 3 months of exercise training using uninterrupted resistance and endurance exercises of the upper extremities. Training was performed 3 times a week on alternating days. RESULTS: Results of graded arm exercise testing showed a 30.3% improvement in peak oxygen consumption (P < .01), a 33.5% increase in time to fatigue (P < .01) and a 30.4% increase in peak power output (P < .05). Pretraining total cholesterol levels (TC) were in the low-risk category and were nonsignificantly lowered following training. Similar nonsignificant reductions of plasma triglycerides averaging 12 mg/dL were attained. Conversely, a 25.9% lowering of LDL-C (P < .05) and 9.8% elevation of HDL-C (P < .05) were observed after training. These changes reduced the average LDL-C-to-HDL-C ratio by 1 unit (P < .05) and the TC-to-HDL-C ratio from 5.0 +/- 1.1 (mean +/- SD) to 3.9 +/- 0.7 (P < .05). CONCLUSIONS: This change reflects a cardiovascular risk reduction of almost 25%; the TC/HDL-C declined from the high-risk score of 5.0 to near the desired score of 3.5. These findings support the beneficial effects of circuit exercise resistance training on fitness and atherogenic lipid profiles in persons with chronic paraplegia.

(Q) SAR study on the metabolic stability of steroidal androgens.

Metabolic stability is a key issue in the development of orally active androgens for Partial Androgen Deficiency in Aging Males (PADAM) and male contraception. Rates of metabolism in human hepatocyte suspensions provide useful information on the stability of compounds that undergo a first pass metabolism. We have derived a structure-pharmacokinetic relationship for a data set of 32 in-house steroidal androgens by means of the decision-trees technique. Volume, shape, number of rotatable bonds, and surface turned out to be the most important descriptors for classification. Only 2 of the 32 compounds were misclassified. The most stable compounds were classified in three leaf nodes on different branches of the tree, suggesting that higher metabolic stability can be achieved for the same substrate by different steric modifications. Further, it is generally assumed that the first step in cytochrome P450s oxidation reactions takes place by hydrogen abstraction to form a radical intermediate. An electronic model for hydrogen abstraction in steroidal androgens was, therefore, developed by means of ab initio calculations. Activation energies of steroid radical systems calculated as energy differences between the reactants equilibrium geometry energies and their corresponding transition states energies could be used to predict relative rates of metabolism to guide the design and redesign process of metabolically more stable steroidal androgens.

Circuit training provides cardiorespiratory and strength benefits in persons with paraplegia.

PURPOSE: This study tested the safety and the effects of circuit resistance training (CRT) on peak upper extremity cardiorespiratory endurance and muscle strength in chronic survivors of paraplegia due to spinal cord injury. METHODS: Ten men with chronic neurologically complete paraplegia at the T5-L1 levels participated in the study. Subjects completed 12 wk of CRT, using a series of alternating isoinertial resistance exercises on a multi-station gym and high-speed, low-resistance arm ergometry. Peak arm ergometry tests, upper extremity isoinertial strength testing, and testing of upper extremity isokinetic strength were all performed before and after training. RESULTS: None of the subjects suffered injury from exercise training. Significant increases were observed in peak oxygen consumption (29.7%, P < 0.01), time to fatigue (P < 0.01), and peak power output during arm testing (P < 0.05). Significant increases in isoinertial strength for the training maneuvers ranged from 11.9% to 30% (Ps < 0.01). Significant increases in isokinetic strength were experienced for shoulder joint internal rotation, extension, abduction, adduction, and horizontal adduction (Ps < 0.05). CONCLUSION: Chronic survivors of paraplegia safely improve their upper extremity cardiorespiratory endurance and muscle strength when undergoing a short-term circuit resistance training program. Gains in fitness and strength exceeded those usually reported after either arm endurance exercise conditioning or strength training in this subject population.

A randomized blinded comparison of two methods used for venous antistasis in tetraplegia.

OBJECTIVE: The hemodynamic effects of slow sequential compression (SCD) were compared with rapid intermittent pulsatile compression (IPC) in subjects with complete tetraplegia. METHODS: Twenty subjects underwent Doppler examination of the bilateral popliteal and femoral veins. Resting volume flow per minute (VFM), average venous velocity (AVV), and maximal venous velocity (MVV) were measured in both veins. SCD and IPC were then randomly applied to one limb each, followed by repeat Doppler measurements under compression conditions. Doppler spectral recordings were stored for future analysis, and then measured by an investigator blinded to testing conditions (rest versus compression) and device (SCD versus IPC). RESULTS: Sequential compression and IPC compression both increased popliteal and femoral vein VFM, AVV, and MVV above resting levels (all p's < 0.001). In the femoral vein VFM (p < 0.05) and MVV (p < 0.05) were augmented during IPC compared to SCD compression. CONCLUSION: As MVV best reflects performance effectiveness of compression devices, these data find IPC more effective than SCD for stimulating venous blood flow in subjects with tetraplegia.

Oxyhemoglobin desaturation and aberrant carbon dioxide homeostasis during electrically stimulated exercise in a ventilator-dependent tetraplegic patient.

This single-subject case examined oxyhemoglobin saturation and alveolar end-tidal carbon dioxide levels in a ventilator-dependent tetraplegic patient undergoing electrical stimulation cycle ergometry. When exercising with a closed tracheostomy cuff under resting ventilator settings (resting intermittent mandatory ventilation; frequency = 6breaths/min, tidal volume = 83.3mL, minute ventilation =5L/min), his oxyhemoglobin saturation decreased from 100% to 92%, while alveolar endtidal carbon dioxide increased linearly to 47mmHg. These undesirable changes were corrected under adjusted intermittent mandatory ventilation conditions (frequency = 12breaths/min, tidal volume = 83.3mL, minute ventilation = 10L/min), during which oxyhemoglobin saturation remained above 98% and the alveolar end-tidal carbon dioxide trend resembled that of ventilator-independent tetraplegic individuals undergoing the same exercise. Because the subject's heart rate was higher under adjusted ventilation conditions, these responses may have been caused by augmented venous return resulting from greater abdominothoracic pumping at the higher breathing frequency. These findings support the need to modify ventilator settings in ventilator-dependent tetraplegic persons while undergoing exercise to maintain oxyhemoglobin saturation and carbon dioxide homeostasis.

Pharmacokinetics and biotransformation of mirtazapine in human volunteers.

This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the area under the plasma drug concentration-time curve (AUC) of mirtazapine in human plasma appeared to be three times higher than the AUC of demethylmirtazapine. As mirtazapine is marketed as a racemic mixture and both enantiomers possess pharmacological properties essential for the overall activity of the racemate, the pharmacokinetics of mirtazapine were examined and appeared to be enantioselective. The R(-)-enantiomer showed the longest elimination half-life from plasma. This was ascribed to the preferred formation of a quaternary ammonium glucuronide of the R(-)-enantiomer. This glucuronide may be deconjugated, leading to a further circulation of the parent compound, thus causing a prolongation in the elimination half-life. The S(+)-enantiomer was preferentially metabolised into an 8-hydroxy glucuronide. Other metabolic transformation pathways found for mirtazapine were demethylation and N-oxidation. Mirtazapine was extensively metabolised and almost completely excreted in the urine (over 80%) and faeces within a few days after oral administration.

Evaluation of a training program for persons with SCI paraplegia using the Parastep 1 ambulation system: part 2. Effects on physiological responses to peak arm ergometry.

OBJECTIVE: To examine the task-nonspecific effects of functional neuromuscular stimulation (FNS)-assisted ambulation training on the physiological responses of persons with paraplegia to upper extremity exercise challenge. DESIGN: Before-after trial. SETTING: Human spinal cord injury (SCI) applied research laboratory. PARTICIPANTS: Twelve men and three women with motor- and sensory-complete thoracic-level SCI (T4-T11), mean age 28.2 +/- 6.8yrs (range, 21.1 to 45.2yrs), mean injury duration 3.7 +/- 3.0yrs (range, 7 to 8.8yrs). INTERVENTION: Thirty-two sessions of FNS ambulation training using a commercial six-channel system (Parastep 1). This system is composed of a microprocessor-controlled electrical stimulation unit and a walking frame outfitted with finger switches that allow the user to independently control the system and stimulation parameters. OUTCOME MEASURES: Peak and subpeak physiological responses to arm ergometry testing and upper extremity strength measures, obtained before and after the FNS ambulation training. RESULTS: Statistically significant increases in peak values for time to fatigue, peak power output, and peak VO2 (all p < .001). Heart rate was significantly lower throughout subpeak levels of arm ergometry after the ambulation training (p < .05). Values of upper extremity strength were not significantly altered after training. CONCLUSIONS: FNS ambulation by persons with SCI paraplegia results in task-nonspecific training adaptations. Central cardiovascular adaptations were indicated as the primary source of these beneficial alterations in exercise responses.

Evaluation of a training program for persons with SCI paraplegia using the Parastep 1 ambulation system: part 1. Ambulation performance and anthropometric measures.

OBJECTIVE: To describe performance parameters and effects on anthropometric measures in spinal cord injured subjects training with the Parastep 1 system. DESIGN: Before-after trial. SETTING: Human spinal cord injury applied research laboratory. PARTICIPANTS: Thirteen men and 3 women with thoracic (T4-T11) motor-complete spinal cord injury: mean age, 28.8yrs; mean duration postinjury, 3.8yrs. INTERVENTION: Thirty-two functional neuromuscular stimulation ambulation training sessions using a commercially available system (Parastep-1). The hybrid system consists of a microprocessor-controlled stimulator and a modified walking frame with finger-operated switches that permit the user to control the stimulation parameters and activate the stepping. OUTCOME MEASURES: Distance walked, time spent standing and walking, pace, circumferential (shoulders, chest, abdomen, waist, hips, upper arm, thigh, and calf) and skinfold (chest, triceps, axilla, subscapular, supraillium, abdomen, and thigh) measurements, body weight, thigh cross-sectional area, and calculated lean tissue. RESULTS: Statistically significant changes in distance, time standing and walking, and pace were found. Increases in thigh and calf girth, thigh cross-sectional area, and calculated lean tissue, as well as a decrease in thigh skinfold measure, were all statistically significant. CONCLUSIONS: The Parastep 1 system enables persons with thoracic-level spinal cord injuries to stand and ambulate short distances but with a high degree of performance variability across individuals. The factors that influence this variability have not been completely identified.

Evaluation of a training program for persons with SCI paraplegia using the Parastep 1 ambulation system: part 3. Lack of effect on bone mineral density.

OBJECTIVE: To determine if the bone mineral density loss seen after spinal cord injury (SCI) is reversed by a walking program using the Parastep 1 system. DESIGN: Before-after trial. SETTING: Human SCI applied research laboratory. PARTICIPANTS: Thirteen men and 3 women with thoracic motor- and sensory-complete SCI, mean age 28.8yrs, mean duration postinjury 3.8yrs. INTERVENTION: Thirty-two functional neuromuscular stimulation (FNS) ambulation training sessions using a commercially available system (Parastep 1). This system consists of a microprocessor-controlled stimulator and a modified walking frame with finger-operated switches that permit the user to control the stimulation parameters and activate the stepping. OUTCOME MEASURE: Bone mineral density at the femoral head, neck, and Ward's triangle measured using a Lunar DP3 dual-photon densitometer. RESULTS: No significant change in bone mineral density was found using repeated measures analyses of variance. CONCLUSIONS: Axial loading combined with muscle stimulation and resistive exercise does not result in significant changes in bone mineral density in persons with complete paraplegia.

Evaluation of a training program for persons with SCI paraplegia using the Parastep 1 ambulation system: part 4. Effect on physical self-concept and depression.

OBJECTIVE: To determine whether persons with spinal cord injury (SCI) paraplegia who participated in an electrical stimulation walking program experienced changes in measures of physical self-concept and depression. DESIGN: Before-after trial. SETTING: Human SCI applied research laboratory. PARTICIPANTS: Volunteer sample of 12 men and 3 women with SCI paraplegia, mean age 28.75 +/- 6.6yrs and mean duration of injury 3.8 +/- 3.2yrs. INTERVENTION: Thirty-two FNS ambulation training sessions using a commercially available system (Parastep 1). The hybrid system consists of a microprocessor-controlled stimulator and a modified walking frame with finger-operated switches that permit the user to control the stimulation parameters and activate the stepping. OUTCOME MEASURES: The Tennessee Self-Concept Scale (TSCS) and the Beck Depression Inventory (BDI) were administered before and after training. Only the Physical Self subscale of the TSCS was analyzed. After training, individual interviews were performed to assess participants' subjective reactions to the training program. RESULTS: A repeated measures analysis of variance indicated that desired directional and statistically significant changes occurred on the Physical Self subscale of the TSCS (F(1,14) = 8.54, p < .011) and on the BDI (F(1,14) = 5.42, p < .035). CONCLUSIONS: Subsequent to the ambulation training program there were statistically significant increases in physical self-concept scores and decreases in depression scores.

Evaluation of a training program for persons with SCI paraplegia using the Parastep 1 ambulation system: part 5. Lower extremity blood flow and hyperemic responses to occlusion are augmented by ambulation training.

OBJECTIVE: To test whether 12 weeks of exercise conditioning using functional neuromuscular stimulation (FNS) ambulation alters the resting lower extremity blood flow and hyperemic responses to vascular occlusion in subjects with paraplegia, and to determine whether an association exists between limb flow and lower extremity fat-free mass. DESIGN: Pretest, posttest. SETTING: Academic medical center. PARTICIPANTS: Subjects with chronic neurologically complete paraplegia. INTERVENTION: Thirty-two sessions of microprocessor-controlled ambulation using electrically stimulated contractions of lower extremity muscles and a rolling walker. OUTCOME MEASURES: Subjects underwent quantitative Doppler ultrasound examination of the common femoral artery (CFA) before and after training. End-diastolic arterial images and arterial flow-velocity profiles obtained at rest and after 5 minutes of suprasystolic thigh occlusion were computer-digitized for analysis of heart rate (HR), CFA peak systolic velocity (PSV), CFA cross-sectional area (CSA), flow velocity integral (FVI), pulse volume (PV), and CFA (arterial) inflow volume (AIV). RESULTS: Significant effects of training on CSA (p < .0001), FVI (p < .05), computed PV (p < .001), and computed AIV (p < .01) were observed. Resting HR was lower following training (p < .05). The change for resting PSV approached but did not reach significance (p = .083). Analysis of postocclusion PV and AIV showed significant effects for conditioning status (p values < .01), postcompression time (p values < .0001), and their interaction (p values < .01). At 1 minute after occlusion, the posttraining AIV response was 78.2% greater in absolute magnitude and 17.4% more robust when expressed as a percentage change from its resting value than before training. Significant correlations were found between thigh fat free mass and both AIV and PV (p values < .05). CONCLUSION: Exercise training using FNS ambulation increases the resting lower extremity AIV in individuals with paraplegia and augments the hyperemic response to vascular occlusion. Improved posttraining blood flow is attributable both to vascular structural changes and upregulation of vascular flow control mechanisms. Limb mass is associated with the volume of arterial blood flow.

Relationships of oxygen uptake, heart rate, and ratings of perceived exertion in persons with paraplegia during functional neuromuscular stimulation assisted ambulation.

Previous reports have described significant limitations in the daily use of functional neuromuscular stimulation (FNS) ambulation systems by persons with spinal cord injuries (SCI). The potential application of these devices to provide physiological benefits as an exercise modality has prompted a reconsideration of the technology. However, the acute physiological effects related to the use of FNS systems have not been thoroughly examined. The purpose of this study was to investigate the relationships of oxygen consumption (VO2), heart rate (HR), and ratings of perceived exertion (RPE) during FNS ambulation by persons with SCI paraplegia. Eleven persons with thoracic level paraplegia, aged 21.5 to 38.0 years, participated in an incremental FNS ambulation test. Metabolic measures were collected continuously via open circuit spirometry as the subjects performed a series of ambulation passes of progressively increasing pace. At the end of each ambulation pass, HR and RPE measures were collected. The test was terminated when either the subjects judged the effort to be maximal or when the investigators deemed the effort to be maximal based on HR. A strong linear relationship was documented between the VO2 and HR measures of all subjects throughout subpeak levels of FNS ambulation. RPE did not vary proportionally with VO2 until relatively high levels of exercise intensity were reached. This study indicates that HR, but not RPE, is an appropriate indicator of exercise intensity for persons with SCI paraplegia using a FNS ambulation system.

Biotransformation of mianserin in laboratory animals and man.

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.

Biotransformation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-H-dibenz[2,3:6,7]oxepin o [4,5-c]pyrrolidine maleate in rats.

The metabolism of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz[2,3:6,7]oxepinol [4,5-c]pyrrolidine maleate (Org 5222) labelled with [3H] or [14C] was investigated in Wistar rats. Metabolites were identified by mass spectrometry, 13C- and 1H-NMR analysis, IR spectroscopy and, wherever possible, by comparison with authentic reference compounds. The metabolites found in plasma, bile, faeces and urine revealed the processes of metabolism in which Org 5222 underwent oxidation to yield an N-oxide existing in two diastereoisomeric forms, or N-demethylation to yield a demethyl metabolite. A novel metabolite was found in bile, viz. a carbamate glucuronide, formed from an intermediate carbamic acid, derived from the addition of CO2 to the demethyl metabolite.

A mass spectrometric approach to the identification of conjugated drug metabolites.

For the identification of intact underivatized drug conjugates, the mass spectrometric technique of choice is fast atom bombardment (FAB); the combined use of both positive and negative ion FAB usually provides information on the molecular mass and nature of conjugates under study, while the number of exchangeable hydrogen atoms can be determined using trideuterated glycerol as the FAB-matrix. Electron impact and desorption chemical ionization spectra can be used to study the aglycone part of the conjugated metabolites. With this approach metabolites conjugated with glucuronic acid, sulphuric acid and amino acids have been identified. The identification was supported by analysis of reference compounds, prepared by chemical synthesis. The examples given are selected from current metabolism studies on drug candidates in development within Organon's research.