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Biomedical subjects

J M Hunter

Publications and source records attributed to J M Hunter.

At least 19 recordsLinked to original sources
PubMed2001

The new neuromuscular blocking agents: do they offer any advantages?

The pharmacodynamics and pharmacokinetics of the two most recent aminosteroid neuromuscular blocking drugs to become available, rapacuronium bromide (Org 9487) and rocuronium bromide are reviewed. Two new classes of drug with neuromuscular blocking properties, the bis-tetrahydroisoquinolinium chlorofumarates and the tropinyl diester derivatives are introduced. Comparisons between these drugs and mivacurium and cisatracurium are made. Rapacuronium 1.5 mg kg(-1) (ED95 1 mg kg(-1)), produces maximal neuromuscular block in 54 s. Time to recovery of the train-of-four ratio to 0.7 is achieved within 20 min after neostigmiine 0.05 mg kg(-1) given at 2 min. The plasma clearance of rapacuronium is 7-8 ml kg(-1) min(-1). Rapacuronium undergoes hepatic metabolism: no prolongation of effect has been reported after a single bolus or a short infusion in patients with hepatic or renal failure. Org 9488 is the 3-desacetyl metabolite of rapacuronium, which has neuromuscular blocking properties. Its much lower clearance (1.28 ml kg(-1) min(-1)) and plasma equilibration constant (0.105 min(-1)) may limit the prolonged use of rapacuronium. Rocuronium given at 2xED95 produces maximal neuromuscular block in 1 min. Spontaneous recovery of the train-of-four ratio to 0.7 takes over 40 min. Rocuronium has a plasma clearance of 4 ml kg(-1) min(-1). Its pharmacodynamics are altered in hepatic and renal disease. A number of anaphylactoid reactions to rocuronium have been reported recently. The bis-tetrahydroisoquinolinium chlorofumarate GW280430A has an ED95 of 0.19 mg kg(-1). Given at three times this dose, onset of neuromuscular block occurs within 100 s; the duration of block is 8-9 min. Following a 2 h infusion, the recovery index does not seem to be increased. Early studies suggest that this drug has no adverse cardiovascular or respiratory side-effects. The tropinyl diester derivative G-1-64 will produce 80-90% neuromuscular block in less than 2 min using 3xED80. Ninety per cent recovery of the first twitch of the train-of-four occurs after 5-7 min using one ED80. A recovery index of less than 2 min has been reported in rats. All the tropinyl diesters appear to produce vagal block.

Aged↗
PubMed2001

Forced expiratory flow in uninfected infants and children born to HIV-infected mothers.

The Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV (P(2)C(2) HIV) Study is a multicenter study examining pulmonary and cardiac outcomes in offspring of HIV-infected mothers. This portion of the P(2)C(2) study tests the hypothesis that infants exposed to, but uninfected by, maternal HIV have normal maximal expiratory flow at functional residual capacity (V'max,(FRC)). We obtained 500 measurements of V'max,(FRC) by rapid thoracic compression in 285 children ages 6-30 mo in five U.S. centers. The data were compared with those from a healthy cohort of children described elsewhere. V'max,(FRC) rose with height in a linear relationship. The slope of the regression line in the exposed infants did not differ statistically from the slope in the comparison group, but the intercept was about 20% lower (p < 0.001). Height and weight were comparable in the two cohorts, and the differences between intercepts persisted after adjusting for birth weight and gestational age. However, maternal HIV infection cannot be assumed to be the cause as the cohorts may have differed in other variables, such as socioeconomic status and frequency of maternal smoking and drug use. Also, measurements varied substantially within and between our five centers, probably in part because of different racial and ethnic distributions. In summary, maternal HIV infection probably has only a modest effect, if any, on maximal expiratory flow at functional residual capacity in uninfected infants.

Age Factors↗
PubMed2000

Metal-assembled cobalt(II) resorc[4]arene-based cage molecules that reversibly capture organic molecules from water and act as NMR shift reagents.

The complex Co4 1(2)8- is a tetranuclear cobalt(II) cage compound that assembles in aqueous solutions above pH 4 and is capable of encapsulating a variety of organic guest molecules, for example, benzene, hexane, chlorobutane, butanol, and ethyl acetate. Ligand 1 is a resorc[4]arene-based molecule with iminodiacetate moieties appended to its upper rim. 1H NMR studies of Co4 1(2)8-.guest complexes demonstrate inclusion of nonpolar hydrocarbons, substituted phenyls, alcohols, halogen-containing hydrocarbons, and polar organic molecules. The complex Co4 1(2)8- acts as an NMR shift reagent and causes substantial upfield isotropic hydrogen shifts (-30 to -40 ppm) in the guest molecule and separation of the guest hydrogen chemical shifts by typically 12 ppm. The complex Co4 1(2)8- will encapsulate molecules with fewer than eight atoms in a linear chain, mono- and disubstituted benzenes, and polar molecules with greater than two carbon atoms. The solid-state structure of Ba4[Co4 1(2).C6H5C2H5] shows a disordered guest molecule encapsulated within the cavity of Co4 1(2)8-. The cavity dimensions, bond lengths, and bond angles of Ba4[Co4 1(2).C6H5C2H5] are very similar to those determined in Ba4[Co4 1(2).6H2O].

Journal Article↗
PubMed2000

Economic development and women's blood pressure: field evidence from rural Mashonaland, Zimbabwe.

A survey of 515 non-pregnant women at 12 geographically chosen research sites in rural Mashonaland shows significant differences in mean blood pressure, controlled by age cohorts. Three levels of economic development are identified: (1) the traditional economy on communal lands, with lowest blood pressure, (2) the wage economy in areas of large-scale commercial agriculture, with elevated blood pressure and (3) the wage economy in mining areas, with the highest elevation of blood pressure. The area is dominated by the primate city, Harare, up to distances of 300 km and beyond, from which forces of change and modernization emanate. It is seen that potassium, sodium and the sodium potassium ratio, are distance-related to Harare and that women's blood pressures tend to follow suit. The rise of body sodium in young persons at risk, often accompanied by declining potassium intake and other changes of modernization, suggest that more attention should be focused on rural areas in Africa, now in the throes of economic change.

Adolescent↗
PubMed2000

Effect of renal failure and cirrhosis on the pharmacokinetics and neuromuscular effects of rapacuronium administered by bolus followed by infusion.

BACKGROUND: Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion. METHODS: During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling. RESULTS: Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium. CONCLUSION: Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.

Adolescent↗
PubMed1999

Laser desorption of DNA oligomers larger than one kilobase from cooled 4-nitrophenol.

A unique matrix system consisting mostly of 4-nitrophenol has shown to be very effective for matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis of large DNA oligomers when a cooled sample stage was used to prevent the sublimation of this matrix under vacuum. Using this 4-nitrophenol matrix with UV laser desorption, detection of picomole quantities of DNA oligomers containing up to approximately 800 nucleotides was routinely achieved. The effectiveness of this matrix was further demonstrated by the observation of a double-stranded DNA oligomer larger than 1000 base pairs, seen as a denatured single-stranded species, with a molecular ion mass exceeding 300 000 Da. The potential applications of 4-nitrophenol as a matrix for DNA sizing are discussed.

DNA↗
PubMed1999

Thoracoabdominal asynchrony and ratio of time to peak tidal expiratory flow over total expiratory time in adolescents with cystic fibrosis.

Thoracoabdominal asynchrony (TAA) and the ratio of time to peak tidal expiratory flow over total expiratory time (TME/TE) have been used to assess airway obstruction in infants and adults. We obtained these measurements using calibrated respiratory inductance plethysmography (RIP) on 15 adolescents and young adults with cystic fibrosis (CF) and varying disease severity. The measurements were then compared to 15 normal age-matched controls. TAA was expressed as a phase angle (phi) calculated from the abdominal (AB) and ribcage (RC) signals acquired from scalar strip chart recordings. Using CODAS (DATAQ Instruments, Akron, OH) software, the analog signals were digitized, and the differentiated sum (AB + RC) signal was used to calculate TME/TE. Forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) were obtained using RIP in all subjects. Subjects with CF had a significantly higher mean phi than the control subjects (15 degrees vs. 8 degrees, respectively, P = 0.01). In the CF patients the specificity of a high phi as an indicator of abnormality was 80%, while the sensitivity was 65%. There was no correlation in the magnitude of phi and disease severity as assessed by FVC or FEV1. There was no significant difference in TME/TE between the groups. We conclude that RIP-acquired phi, but not TME/TE, is a simple and useful method to detect the presence of airway obstructive disease. We speculate that the sensitivity of this method will increase in younger patients with more compliant chest walls and less air trapping. Longitudinal studies of phi in infants and young children with lung disease could help in assessing disease severity and progression in this population, in whom repeated measures are few and complex.

Abdomen↗
PubMed1999

Single nucleotide polymorphism determination using primer extension and time-of-flight mass spectrometry.

The high frequency of single nucleotide polymorphisms (SNPs) in the human genome makes them a valuable source of genetic markers for identity testing, genome mapping, and medical diagnostics. Conventional technologies for detecting SNPs are laborious and time-consuming, often prohibiting large-scale analysis. A rapid, accurate, and cost-effective method is needed to meet the demands of a high-throughput DNA assay. We demonstrate here that analysis of these genetic markers can now be performed routinely in a rapid, automated, and high-throughput fashion using time-of-flight mass spectrometry and a primer extension assay with a novel cleavable primer. SNP genotyping by mass spectrometry involves detection of single-base extension products of a primer immediately adjacent to the SNP site. Measurement of the mass difference between the SNP primer and the extension peak reveals which nucleotide is present at the polymorphic site. The primer is designed such that its extension products can be purified and chemically released from the primer in an automated format. The reduction in size of the products as a result of this chemical cleavage allows more accurate identification of the polymorphic base, especially in samples from a heterozygotic population. All six possible heterozygotes are resolved unambiguously, including an A/T heterozygote with extension products differing by only 9 Da. Multiplex SNP determination is demonstrated by simultaneously probing multiple SNP sites from a single polymerase chain reaction (PCR) product as well as from multiplexed PCR amplicons. Samples are processed in parallel on a robotic workstation, and analyzed serially in an automated mass spectrometer with analysis times of only a few seconds per sample, making it possible to process thousands of samples per day.

DNA Primers↗
PubMed1999

Anaesthesia for Conn's syndrome.

We describe the peri-operative management of two patients undergoing bilateral adrenalectomy for Conn's syndrome; one using an open surgical approach and the other a laparoscopic technique. The first patient, aged 64 years, died of a myocardial infarction 5 days postoperatively; the second, aged 29 years, had an uneventful recovery. The pre-operative preparation, peroperative management and postoperative care of these patients are detailed, and the pathophysiology and clinical management of Conn's syndrome are reviewed.

Adrenalectomy↗
PubMed1999

Antagonism of rapacuronium using edrophonium or neostigmine: pharmacodynamics and pharmacokinetics.

We have studied the pharmacodynamics and pharmacokinetics of rapacuronium (Org 9487) in 70 healthy patients. Neuromuscular transmission was monitored using TOF stimulation of the ulnar nerve and mechanomyography of the adductor pollicis muscle. Half of the patients were given a single dose of rapacuronium 1.5 mg kg-1 and the remainder rapacuronium 1.5 mg kg-1 with three incremental doses of 0.5 mg kg-1, each given when T1/T0 had recovered to 25%. In all patients, neuromuscular block was antagonized using neostigmine 0.05 mg kg-1 or edrophonium 1.0 mg kg-1 (allocated randomly), 2 min after the final dose of rapacuronium. All patients developed complete block after rapacuronium 1.5 mg kg-1. Mean onset time was 66 (SD 24) s. In patients who received an antagonist 2 min after the first dose of rapacuronium, time to recovery of T1/T0 to 25% was similar after neostigmine (9.8 (3.8) min) and edrophonium (10.3 (4.3) min): in patients who received incremental doses of rapacuronium, spontaneous recovery of T1/T0 to 25% after the first dose was 18.9 (4.7) min. In those who received an antagonist 2 min after the first dose of rapacuronium, times to recovery of T4/T1 to 0.7 were also similar after neostigmine (23.7 (7.7) min) and edrophonium (29.1 (10.7) min). After three incremental doses of rapacuronium, there was a longer time to recovery of T1/T0 = 25% after neostigmine compared with edrophonium (5.1 (1.0) vs 3.3 (1.3) min; P < 0.05) but more rapid recovery to T1/T0 = 75% (10.1 (2.9) vs 16.8 (10.1) min; P < 0.05) and T4/T1 = 0.7 (19.8 (6.3) vs 35.1 (10.4) min; P < 0.05). A three-compartment pharmacokinetic model was justified. Typical values for clearance and initial volume of distribution (V1) were 4.4 ml kg-1 min-1 and 94.8 ml kg-1, respectively. In females, clearance was decreased by 38.5% compared with males and V1 was decreased by 25% in patients aged more than 65 yr.

Adolescent↗
PubMed1999

Clinical pharmacokinetics of the newer neuromuscular blocking drugs.

The pharmacokinetics of 6 new neuromuscular blocking drugs are described. These are the aminosteroids pipecuronium bromide, rocuronium bromide and rapacuronium bromide (ORG-9487) and the benzylisoquinolinium diesters doxacurium chloride, mivacurium chloride and cisatracurium besilate. In healthy individuals, these drugs all have similar volumes of distribution. Their pharmacokinetics are influenced little by age or anaesthetic technique, but renal and hepatic disease may significantly alter their distribution and elimination. Pipecuronium resembles pancuronium in its pharmacokinetic and neuromuscular blocking profile, but is devoid of cardiovascular effects. It has a low clearance (0.16 L/h/kg) and long elimination half-life (120 minutes). It is largely eliminated through the kidney. Rocuronium has a similar pharmacokinetic profile to vecuronium but its onset of action is more rapid and duration of action slightly shorter. Its clearance (0.27 L/h/kg) is intermediate between those of pipecuronium and rapacuronium, but its elimination half-life is long (83 minutes). The pharmacokinetics of rocuronium are altered by renal and hepatic disease; the latter probably has the more significant effect. Rapacuronium has a rapid onset, and a bolus dose has a short duration of action. It has a high clearance (0.59 L/h/kg) but a long elimination half-life (112 minutes). Doxacurium has a pharmacokinetic and pharmacodynamic profile similar to pipecuronium. It has a high potency and is devoid of cardiovascular effects. In adults, it has a low clearance (0.15 L/h/kg) and long elimination half-life (87 minutes). Mivacurium is a mixture of 3 stereoisomers. It has a short to intermediate duration of action. It is hydrolysed by plasma cholinesterase. Inherited or acquired alterations in plasma cholinesterase activity are associated with changes in the pharmacokinetics and time course of action of mivacurium. The 2 active isomers (cis-trans and trans-trans) have a high clearance (4.74 L/h/kg) and very short elimination half-lives (approximately 2 minutes). Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. It has similar pharmacokinetics and pharmacodynamics to atracurium. It is mainly broken down by Hofmann (non-enzymatic) degradation. Cisatracurium has an intermediate clearance (0.3 L/h/kg) and short elimination half-life (26 minutes). Hepatic and renal disease have little effect on its pharmacokinetics.

Aging↗