Composition of, and [14C]acetate incorporation into, lipids of rat Sertoli cells in culture.

Primary cultures of rat Sertoli cells were used for the determination of their lipid and fatty acid composition and for a demonstration of their ability to incorporate 14C from [14C]acetate into fatty acids esterified in the cellular lipids. Similar fatty acid compositions were observed in 9-day cultures of Sertoli cells of rats aged 3, 4 or 5 weeks. Cultures of Sertoli cells of 5-week-old rats had relatively less palmitic, linoleic and arachidonic acids and more palmitoleic, stearic, oleic and docosatetraenoic acids than non-cultured cells from the same pool. No difference between these was observed in phospholipid concentration, but the cultured cells had a greater concentration of both total cholesterol and triacylglycerols than did the non-cultured cells. 14C from [14C]acetate added to the culture medium on the 7th (48-h incubation) or 8th (24-h incubation) day was incorporated into fatty acids esterified in cellular lipids. Major incorporation was into phospholipids and triacylglycerols, but cholesterol also was labeled. The fatty acids containing most of the 14C were the saturated fatty acids, oleic acid and docosatetraenoic acid (products of both de novo synthesis and elongation reactions).

Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis.

OBJECTIVES: We tested the hypotheses that (1) plasma clearance of dichloroacetate is decreased in patients with end-stage cirrhosis, and (2) patients with cirrhosis are vulnerable to dichloroacetate-induced hypoglycemia caused by exaggerated inhibition of hepatic glucose production. METHODS: Seven subjects with cirrhosis and six healthy volunteers received a 5-hour primed constant infusion of 6,6-2H2-glucose. After a 2-hour basal period, subjects received intravenous dichloroacetate, 35 mg/kg, over 30 minutes. Dichloroacetate pharmacokinetics were compared by the mixed-effects population-based technique. Glucose production was calculated by means of isotope dilution. RESULTS: The optimal dichloroacetate pharmacokinetic model for both subjects with cirrhosis and control subjects had two compartments, with all parameters weight normalized. Peak plasma dichloroacetate concentration in subjects with cirrhosis did not differ from that in control subjects, but typical dichloroacetate clearance was only 36% of that in control subjects (P < .001). Dichloroacetate decreased plasma lactate concentration by approximately 50% (P < .001), glucose production by 7% to 9% (P < .05), and plasma glucose concentration by 9% to 14% (P < .05) in both subjects with cirrhosis and control subjects. Dichloroacetate-induced decreases in plasma lactate and glucose concentrations and in glucose production in subjects with cirrhosis did not differ from those in control subjects. CONCLUSIONS: Plasma dichloroacetate clearance is markedly decreased in patients with cirrhosis, likely because of compromised hepatic function. Subjects with cirrhosis exhibit neither exaggerated inhibition of glucose production nor increased risk of hypoglycemia as a result of acute dichloroacetate-induced hypolactatemia.

Can bioavailability of low-variance drugs be estimated with an unpaired, sparse sampling design?

OBJECTIVE: Bioavailability (F) with nonintravenous administration is traditionally estimated by comparison of the area under the plasma concentration versus time curve (AUC) after drug administration by each of the nonintravenous and intravenous routes in the same individual. This paired approach may not always be possible. We simulated whether F and the absorption rate constant (ka) could be estimated accurately for a drug with low variance using different patients for nonintravenous and intravenous routes and whether sparse sampling permitted accurate estimates. METHODS: Using pharmacokinetic parameters for cisatracurium besylate (INN, cisatracurium besilate), we simulated data sets representing 20 administrations (10 intravenous and 10 nonintravenous) with either three (sparse) or 16 (extensive) samples per administration. Simulations were performed twice, with ka values of 0.1 (slow absorption) or 0.3 (rapid absorption) min-1. With use of NONMEM, we estimated F and ka for each data set using both two-stage and mixed-effects modeling approaches and paired and unpaired designs to determine the percentage of estimates that deviated > 25% from the simulated value. RESULTS: Estimates of F with extensive data were satisfactory for all approaches. With sparse sampling, two-stage analysis of unpaired data were not possible, two-stage analysis of paired data yielded erroneous estimates, and mixed-effects modeling gave satisfactory estimates. Estimates of ka were sometimes erroneous with all approaches except for paired analysis of extensive data with slow absorption; sparse data and two-stage analysis increased the likelihood of errors compared with extensive data and mixed-effects modeling. CONCLUSIONS: Mixed-effects modeling facilitates estimation of F and ka for low-variance drugs in situations in which traditional paired extensive data designs are not possible.

Vecuronium kinetics and dynamics in anesthetized infants and children.

Vecuronium kinetics and dynamics were determined in five infants (3 to 11 months old) and five children (1 to 5 years old) during anesthesia with 70% nitrous oxide and 0.9 MAC halothane. Vecuronium was infused intravenously at a rate of 2.5 micrograms/kg/min while twitch tension of the adductor pollicis muscle was recorded and venous blood samples were drawn for determination of vecuronium concentrations by mass spectrometry. The elimination t1/2 was determined by linear regression of the log postdistribution concentration-time data; these values and noncompartmental techniques were used to calculate total plasma clearance (Cl), volume of distribution at steady state (Vdss), and mean residence time. The steady-state plasma concentration resulting in 50% depression of twitch tension (Cpss50) was determined by an effect compartment and a sigmoid concentration vs. paralysis model. Vdss was larger in infants (357 +/- 70 ml/kg; mean +/- SD) than in children (204 +/- 116 ml/kg), and Cl was of the same order for infants and children (5.6 +/- 1.0 and 5.9 +/- 2.4 ml/kg/min). Mean residence time was longer in infants (66.3 +/- 22.9 minutes) than in children (34.3 +/- 8.0 minutes). Cpss50 was lower in infants (57 +/- 18 ng/ml) than in children (110 +/- 28 ng/ml). The quantity of vecuronium in the body at steady state at 50% depression of twitch tension (Vdss X Cpss50) was similar in infants and children (21.2 +/- 9.9 and 19.0 +/- 3.3 micrograms/kg). During comparable nitrous oxide-halothane anesthesia, age-related changes in Vdss, Cl, and Cpss50 were much like those found for d-tubocurarine.(ABSTRACT TRUNCATED AT 250 WORDS)

Opioid pharmacodynamics in neonatal dogs: differences between morphine and fentanyl.

Clinical experience and laboratory studies suggest that neonates are more sensitive than adults to the ventilatory depressant effects of morphine. Similar sensitivity has been cited, but not demonstrated, for fentanyl. To examine this issue, we determined ventilatory pharmacodynamics of morphine and fentanyl in 28 dogs aged 2-35 days. During isohypercapnia, morphine or fentanyl was infused to depress minute ventilation by > 50% and arterial plasma opioid concentrations were measured. For each drug, an effect compartment pharmacodynamic model was fit to the values for minute ventilation to determine the steady-state opioid plasma concentration depressing ventilation by 50% (C50) and the rate constant for equilibration between plasma concentration and effect (keo). For morphine, there was a marked age-related increase in C50 but no change in keo. For fentanyl, there was a small maturational increase in C50 and no change in keo. We conclude that there are marked maturational changes in the ventilatory depressant effects of morphine resulting from maturational changes in sensitivity rather than in equilibration. Maturational changes in the ventilatory effects of fentanyl are much smaller in magnitude than those for morphine.

Descriptive anatomy of fibrocartilaginous menisci in the finger joints of the hand.

Observations were made from the dissection of 156 digital joints (thumbs excluded). In all joints fibrocollagenous menisci projected into the articular cavity from a ring-like structure based on the joint capsule. These meniscal structures separated the articulating cartilage surfaces at the margins of the joint. Histological examination confirmed a fibrocartilaginous nature of the tissue which demonstrated positive staining for proteoglycans and collagen fibers. Although generally similar in form, these meniscal structures varied in extent when compared between joint groups. The greatest amount and articular contribution was noted in metacarpophalangeal joints with least being found distally.

The effect of isoflurane versus balanced anesthesia on rocuronium's pharmacokinetics and infusion requirement.

STUDY OBJECTIVE: To compare the effects of two anesthetic techniques, balanced and isoflurane anesthesia, on the response to an intubating dose and an infusion of rocuronium, and on rocuronium's pharmacokinetics. DESIGN: Randomized, open-label study. SETTING: A university-affiliated hospital. PATIENTS: Twenty-two healthy adults undergoing elective surgery. INTERVENTIONS: The patients were anesthetized with a balanced technique (nitrous oxide, fentanyl, midazolam) or isoflurane (nitrous oxide, isoflurane 0.5-1.0%). Rocuronium was administered initially as a 500-micrograms/kg bolus, then by infusion to maintain approximately 86-94% depression of twitch tension. Plasma samples to determine rocuronium concentrations were obtained before, during, and after the infusion. Pharmacokinetics were determined using a population-based approach. MEASUREMENTS AND MAIN RESULTS: Onset time and initial recovery after the bolus dose were similar for the two groups. Infusion requirements also were similar. Plasma clearance was greater during isoflurane than during balanced anesthesia (4.48 vs 3.49 ml/kg/min). Distribution clearances and volumes of distribution were similar for the two groups. CONCLUSIONS: The similarity of response to an intubating dose and an infusion of rocuronium suggests that clinicians need not alter the dose or rate of rocuronium administration during isoflurane anesthesia with a of duration less than 1 hour. However, the greater clearance of rocuronium, in light of the similarity of infusion requirements, suggests that isoflurane potentiates rocuronium compared with balanced anesthesia.

The management of pain associated with pediatric procedures.

This article provides guidelines for the psychological and pharmacologic management of pain and anxiety for children undergoing medical procedures. The goals of intervention are presented, as well as issues warranting consideration in planning intervention to reduce procedure-related distress.

Clinical pharmacology of neuromuscular blocking agents.

The clinical pharmacology of neuromuscular blocking agents is described. During neuromuscular blockade, succinylcholine attaches to receptors in the motor end plate and depolarizes the neuromuscular junction, making the end plate refractory to acetylcholine. The nondepolarizing relaxants have a structure similar to that of succinylcholine and bind to the same receptors. Instead of depolarizing the junction, they block acetylcholine from binding to the receptor and cause channel blockade. As the concentration of nondepolarizing relaxant increases relative to acetylcholine, neuromuscular transmission is compromised. This relationship is used clinically to facilitate recovery from nondepolarizing agents. Succinylcholine is popular because its onset is faster than that of the nondepolarizing relaxants and metabolism by pseudocholinesterase clears it quickly. It is commonly given as an i.v. bolus to facilitate tracheal intubation. The onset of these agents varies widely and is dose dependent. Large doses are usually given to hasten the onset of paralysis; subsequent doses are adjusted according to response. The nondepolarizing agents interact with inhaled anesthetics, magnesium, and many antimicrobials. Drugs like neostigmine, edrophonium, and pyridostigmine antagonize neuromuscular blockade; an anticholinergic drug is typically administered to counteract the cardiovascular effects. The most serious adverse effects of succinylcholine are malignant hyperthermia syndrome, masseter muscle rigidity, and bradycardia. Some nondepolarizing relaxants (atracurium, mivacurium, and pancuronium) are associated with histamine release, occasionally causing serious hypotension and tachycardia. Neuromuscular blocking agents are essential to anesthesia. Older compounds produce greater toxicity than newer compounds, and several of these older compounds therefore are no longer in clinical use.

Bilateral buccal flaps with double opposing Z-plasty for wider palatal clefts.

Described is a technique that has evolved from the challenges of closure of larger cleft palate defects and that we are now using in preference over other techniques to repair a wide variety of clefts. Soft-palate closure and muscular sling reconstruction are accomplished using a modified Furlow technique. An associated cleft of the hard palate and the gaps produced by posterior displacement of the reconstructed soft palate are closed by adding tissue, buccal flaps, rather than by closure under tension or leaving residual raw surfaces. Palate lengthening is achieved both by the Z-plasty effect and by the interposition of buccal flaps between the hard and soft palate. Seventy-six palates have been repaired using this procedure. There were three postoperative fistulas.

A model for the cleft lip nasal deformity.

The underlying pathology of the cleft lip nasal deformity has yet to be fully realized, and cleft lip rhinoplasty continues to challenge the reconstructive surgeon. A new model is proposed, which is composed of elements that represent known anatomical structures of the nose. These structures are considered elemental to the mechanism of the primary cleft lip nasal deformity. The lobule is reduced to four arches. Five points on the skull provide foundations for these arches, which react interdependently to extrinsic forces and positional change. When certain changes are imposed on the model, predictable alterations in the configuration of the model imitate the observed deformities in the spectrum of the cleft lip nasal deformity, unilateral and bilateral, mild through severe. The model is described with illustrations, anatomic dissection, physical models, and selected clinical cases. A better understanding of the mechanisms of the cleft nasal deformities can be obtained through analysis of the model.

Transcutaneous PO2 of the scalp in male pattern baldness: a new piece to the puzzle.

Our study was designed to measure the transcutaneous PO2 of the scalp to determine if there was a relative microvascular insufficiency and associated tissue hypoxia in areas of hair loss in male pattern baldness. A controlled prospective study was performed at Butterworth Hospital, Grand Rapids, Michigan. Eighteen nonsmoking male volunteers aged 18 years and older were studied. Nine men had male pattern baldness (Juri degree II or III), and nine were controls (no male pattern baldness). Scalp temperature and transcutaneous PO2 were obtained at frontal and temporal sites in each subject. Peripheral circulation was assessed from postocclusive transcutaneous PO2 recovery time by means of maximum initial slope measurements. Statistical significance was assessed at p < 0.05. There was no significant difference in scalp temperature between male pattern baldness subjects and controls. Temporal scalp blood flow was significantly higher than frontal scalp blood flow in male pattern baldness subjects; however, there was no significant difference in controls. Transcutaneous PO2 was significantly lower in bald frontal scalp (32.2 +/- 2.0 mmHg) than in hair-bearing temporal scalp (51.8 +/- 4.4 mmHg) in men with male pattern baldness. In controls, there was no significant difference in transcutaneous PO2 of frontal scalp (53.9 +/- 3.5 mmHg) and temporal scalp (61.4 +/- 2.7 mmHg). Transcutaneous PO2 also was significantly lower in the frontal scalp of male pattern baldness subjects (32.2 +/- 2.0 mmHg) than in either frontal or temporal scalp of controls (53.9 +/- 3.5 mmHg and 61.4 +/- 2.7 mmHg, respectively). There is a relative microvascular insufficiency to regions of the scalp that lose hair in male pattern baldness. We have identified a previously unreported tissue hypoxia in bald scalp compared with hair-bearing scalp.

The incidence and degree of scleral show in the normal population.

The degree and incidence of scleral show in a normal population was studied in 100 Caucasian patients. Subjects were fitted with a headband goniometer. The goniometer was related to a standard anatomic landmark (the Frankfort plane), and the subject's head was inclined through angles of 0 to -35 degrees. With the subject fixing on a constant point, the degree of white showing between the lower eyelid and the limbus was measured. The results demonstrated that scleral show was a normal finding, the degree of which increases with increasing inclination of the head from the Frankfort plane. No sex variation or increase with age was noted.

Three-dimensional computed tomographic analysis of the primary nasal deformity in 3-month-old infants with complete unilateral cleft lip and palate.

The purpose of this study was to analyze the geometry of the primary cleft lip nasal deformity using three-dimensional computerized tomography in a group of 3-month-old infants with complete unilateral cleft lip and palate before surgical intervention. Coordinates and axes were reconfigured after the three-dimensional image was oriented into neutral position (Frankfurt horizontal, true anteroposterior, and vertical midline). Display and measurement of skin surface and osseous tissues were achieved by adjusting the computed tomographic thresholds. S-N, N-ANS, S-N-O, and S-N-ANS were measured from true lateral views. Biorbital (LO-LO), interorbital (MO-MO), intercanthal (en-en), and nasal (al-al) widths were measured from the anteroposterior view. The bony alveolar cleft width was measured from the inferior view. The study group was divided into two groups on the basis of skeletal alveolar cleft width: six patients with clefts narrower than 10 mm and six patients with clefts wider than 10 mm. Only the S-N-ANS angle differed between the two groups, i.e., it was greater in the group with the wider clefts (p < 0.05). Coordinates of six landmarks at the base of the nose [sellion (se), subnasale (sn), cleft-side and noncleft-side subalare (sbal-cl and sbal-ncl), and the most posterior point on the lateral piriform margins (PPA-CL and PPA-NCL)] were obtained for analysis of the nasal deformity. On average, the subnasale point was anterior to sellion and deviated to the noncleft side; the cleft-side sbal point was more medial, posterior, and inferior than the noncleft-side sbal point; and the PPA point on the cleft-side piriform margin was more lateral, posterior, and inferior than the PPA point on the noncleft side. These discrepancies were not universally observed. However, in all patients, four findings were observed without exception (p < 0.01): (1) subnasale (sn) was deviated to the noncleft side (mean distance from midline, 5.0 mm; range, 2 to 9.5 mm), (2) the cleft-side alar base (sbal-cl) was more posterior than the noncleft-side alar base (sbal-ncl) (mean difference, 3.6 mm; range, 1 to 5.5 mm), (3) the noncleft-side alar base (sbal-ncl) was further from the midline than the cleft-side alar base (sbal-cl) (mean difference in lateral distances of sbal-ncl and sbal-cl from the midline, 2.8 mm; range, 0.5 to 7 mm), and (4) the cleft-side piriform margin (PPA-CL) was more posterior than the noncleft side piriform margin (PPA-NCL) (mean difference, 2.1 mm; range, 0.5 to 4 mm). In conclusion, the nasal deformity in unilateral cleft lip and palate that has not been operated on is characterized by these four features and increased S-N-ANS angle with increased alveolar cleft width.

Major childhood tumor resection using normovolemic hemodilution anesthesia and hetastarch.

Acute normovolemic hemodilution is a safe technique for minimizing operative blood loss during major tumor resection in children. Based on our experience using hemodilution anesthesia in 14 successful extensive tumor resections, we conclude the following: (1) this is an effective means of reducing use of bank blood and thus avoiding the risks of multiple transfusions; (2) it facilitates surgical dissection due to increased visibility with dilute blood, and decreased bleeding due to controlled hypotension; (3) this technique is acceptable for Jehovah's Witnesses; (4) hetastarch is an effective, inexpensive colloid hemodiluent which minimized perioperative edema compared to crystalloid hemodilution.

The organization of spontaneous leg movements in newborn infants.

Spontaneous, supine kicking in newborn (2- and 4-week-old) infants is described in terms of its temporal structure, interjoint coordination, and muscle activation characteristics as measured by surface electromyography. Phasic kick movements shoed a constrained temporal organization in the movement, but not the pause phases. Hip, knee, and ankle joints moved in temporal and spatial synchrony, and all three joints showed a rhythmical or periodic organization over time. EMGs revealed antagonist coactivation at the initiation of the flexor movement, but little or not extensor activity. The dorsal muscles, the gastrocnemius and hamstrings, showed less activity than the ventral pair, tibialis anterior and quadriceps. Burst and onset-to-peak durations were also constrained. As a result of neural mechanisms and biomechanical forces, newborn leg movements are structured muscle synergies. This organization has implications both for newborn functioning and for later development.

Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.

Alvimopan, a mu-opioid antagonist without anti-analgesic effects, is being developed to manage postoperative ileus. We characterized the population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

Neuromuscular blocking agents in paediatric anaesthesia.

Neuromuscular blocking agents are used commonly in paediatric anaesthesia, both to facilitate tracheal intubation and during surgery. Paediatric patients differ from adults in certain pharmacokinetic and pharmacodynamic characteristics. However, because maturational changes in certain of these characteristics counterbalance, dosing requirements do not differ markedly with age. In general, onset is more rapid in paediatric patients than in adults. Succinylcholine is still used commonly in children, despite restrictions by regulatory authorities, because of its rapid onset and offset. However, newer non-depolarizing neuromuscular blocking agents, particularly mivacurium, rocuronium and rapacuronium, offer many of the advantages of succinylcholine without its severe adverse effects: rocuronium and rapacuronium have an onset comparable with that of succinylcholine whereas the onset of mivacurium is slightly longer. In addition, recovery from an intubating dose of either mivacurium or rapacuronium is nearly comparable with that of succinylcholine. If rapacuronium i.m. proves to have a rapid onset without prolonged duration, the remaining value of succinylcholine will diminish.