UPDATED AGE-SPECIFIC EXTERNAL DOSE AND EXPOSURE RATE COEFFICIENTS FOR 131I PATIENT RELEASE.

Updated effective dose rate and exposure rate coefficients for age-specific receptors representing members of the public were computed for external exposures from age-specific patients administered 131I to treat thyroid dysfunction for patient release evaluation. Coefficients were compared to the simplified point source method described by United States Nuclear Regulatory Commission Regulatory Guide (RG) 8.39, which does not consider age-specific parameters, morphometry or time-dependent 131I biodistribution. Monte Carlo age-specific phantom simulations were correlated with modified continuous voiding patient biokinetic models approximating age-specific dose and exposure rates as a function of time postadministration. Dose rates resulted in an overapproximation by a factor of ~3 from differentiated thyroid cancer patients (5% uptake) and by ~2 from hyperthyroid patients (80%) at 8 h postadministration compared to RG8.39. This study provides a paradigm where age-specific morphometry and biokinetic integration must be jointly considered when developing patient release guidelines for 131I and future radionuclide therapies.

Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes.

Asexual proliferation of the Plasmodium parasites that cause malaria follows a developmental program that alternates non-canonical intraerythrocytic replication with dissemination to new host cells. We carried out a functional analysis of the Plasmodium falciparum homolog of Protein Phosphatase 1 (PfPP1), a universally conserved cell cycle factor in eukaryotes, to investigate regulation of parasite proliferation. PfPP1 is indeed required for efficient replication, but is absolutely essential for egress of parasites from host red blood cells. By phosphoproteomic and chemical-genetic analysis, we isolate two functional targets of PfPP1 for egress: a HECT E3 protein-ubiquitin ligase; and GCα, a fusion protein composed of a guanylyl cyclase and a phospholipid transporter domain. We hypothesize that PfPP1 regulates lipid sensing by GCα and find that phosphatidylcholine stimulates PfPP1-dependent egress. PfPP1 acts as a key regulator that integrates multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.

Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans.

Apicomplexans invade a variety of metazoan host cells through mechanisms involving host cell receptor engagement and secretion of parasite factors to facilitate cellular attachment. We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. Using reverse-genetic and chemical-genetic approaches, we determine that calcineurin critically regulates and stabilizes attachment of extracellular P. falciparum to host erythrocytes before intracellular entry and has similar functions in host cell engagement by T. gondii. Calcineurin-mediated Plasmodium invasion is strongly associated with host receptors required for host cell recognition, and calcineurin function distinguishes this form of receptor-mediated attachment from a second mode of host-parasite adhesion independent of host receptors. This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans.

Ibuprofen sodium is absorbed faster than standard Ibuprofen tablets: results of two open-label, randomized, crossover pharmacokinetic studies.

BACKGROUND: A novel ibuprofen (IBU) formulation, Advil(®) Film-Coated Tablets (IBUNa), was developed. OBJECTIVE: Pharmacokinetic comparison of IBUNa versus other IBU formulations. STUDY DESIGN: Two randomized, single-dose, open-label, five-way crossover pharmacokinetic studies. SETTING: Inpatient research clinic. SUBJECTS: Seventy-one healthy adult volunteers. INTERVENTION: Study 1: In three periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) Liqui-Gels(®) (IBULG) 2 × 200 mg, and Motrin(®) IB (IBUMot) 2 × 200 mg tablets. In two periods following a high-fat breakfast, subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg and IBULG 2 × 200 mg. Study 2: In five study periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) FastGel(®) (IBUFG) 2 × 200 mg, Nurofen(®) (IBUNur) 2 × 200 mg, Advil(®) (IBUAdv) 2 × 200 mg, and Nurofen(®) Express containing IBU lysinate (IBULys) 2 × 342 mg. MAIN OUTCOME MEASURE: Log-transformed area under the plasma concentration versus time curve to last observable concentration (AUCL) and maximum plasma concentration (C max) were the primary pharmacokinetic parameters; time to maximum measured plasma concentration (T max) was analyzed post hoc. RESULTS: IBUNa was bioequivalent to IBULG (fasted and fed) and IBUFG and IBULys (fasted) for rate (C max) and extent (AUCL) of IBU absorption. After fasting, AUCL was bioequivalent for IBUNa and IBUMot, IBUAdv, and IBUNur, but C max occurred significantly earlier with IBUNa. After fasting, median IBUNa T max was comparable to that for IBULG, IBUFG, and IBULys, but was much shorter than that for IBUMot, IBUNur, and IBUAdv. Food slowed absorption of IBUNa and IBULG similarly. All treatments were tolerated similarly. CONCLUSION: IBUNa is absorbed faster but to a similar extent as standard IBU formulations.

Quantification of nebivolol hydrochloride in human plasma by liquid chromatography using fluorescence detection: Use in pharmacokinetic study.

A simple, rapid, and sensitive method of reversed-phase high-performance liquid chromatography with fluorescence detection has been developed and validated for use in determining levels of nebivolol•HCl in human plasma. Sample preparation involves a simple single-step protein precipitation procedure and extraction of nebivolol in acetonitrile. The separation was performed on a Kromasil® RP-C18 column (Ф 4.6 mm × 250 mm, 5 µm) with a mobile phase consisting of 0.05 M potassium dihydrogen phosphate buffer/acetonitrile (40:60, v/v) adjusted to pH 3 using orthophosphoric acid. Analysis was carried out under isocratic conditions at a flow rate of 1.5 mL/min and at room temperature using a fluorescence detector with excitation at 288 nm and emission at 310 nm. The chromatographic run was 4 min. The calibration curve was linear over the concentration range 0.2-20 ng/mL. The method was validated in terms of its accuracy, precision, and specificity. The assay enabled the measurement of nebivolol with a minimum quantification limit of 0.16 ng/mL. The average recovery of nebivolol from spiked human plasma was 98.4 ± 3.3%. This method was successfully used in a pharmacokinetic study of oral administration of 5-mg tablets to healthy human volunteers.

The detection of Plasmodium falciparum and P. vivax in DNA-extracted blood samples using polymerase chain reaction.

Seventeen pairs of published primer sets were compared for their relative sensitivity to detect malaria DNA extracted from blood samples, which were obtained from Pakistani patients suffering from malaria. The primer sets investigated consisted of: (i) 9 pairs of direct primers and 3 sets of nested primers for detecting Plasmodium falciparum, (ii) 2 pairs of direct primers and 2 sets of nested primers for detecting P. vivax, and (iii) 1 set of multiplex primers for detecting both P. falciparum and P. vivax, simultaneously. After a miniscreen of 9 DNA-extracted blood samples using the 17 primer sets stated above, 5 primer sets were short-listed (based on their superior sensitivity) and used for a maxi-screen of DNA extracted from 126 microscopy-positive blood samples from Pakistan, with the following results. (i) For the detection of P. falciparum, the direct primer pair 'PF1 + PF2' gave a sensitivity of 95% and the nested primer set 'RIT405 + RIT406/RIT371 + RIT372' gave a sensitivity of 97%. (ii) For the detection of P. vivax, the direct primer pair 'Forward + Reverse' and the nested primer set 'PLF + UNR/PLF + VIR' both gave a sensitivity of 94%. (iii) The nested multiplex primer set 'rPLU5 + rPLU6/rFAL1 + rFAL2 + rVIV1 + rVIV2' gave a sensitivity of 97% and 96% for P. falciparum and P. vivax, respectively. It was concluded that the nested multiplex primer set was the most optimal primer set to use for the detection of malaria DNA extracted from blood samples. Furthermore, the nested multiplex primer set has the advantage of simultaneously detecting and differentiating between P. vivax and P. falciparum.

The effect of priming with vecuronium and rocuronium on young and elderly patients.

UNLABELLED: The priming principle consists of administering a subparalyzing dose of nondepolarizing neuromuscular blocking drug 3-6 min before giving a second dose for tracheal intubation. This study was performed to observe the effects of priming doses of vecuronium and rocuronium on pulmonary function tests and muscular weaknesses in young (25-35 yr of age) and elderly (65-73 yr of age) patients. Ten young and 10 elderly patients were each placed in vecuronium and rocuronium groups. Oxygen saturation and train-of-four (TOF) ratio were determined, and pulmonary function tests were performed. Then 20% of the 95% effective dose (ED95) of the muscle relaxants was given intravenously. All tests were performed again 4 min after vecuronium and 3 min after rocuronium. Other signs of muscular weaknesses were also recorded. Elderly patients showed more signs of muscle weakness in both groups. The TOF ratio was 0.77 and 0.79 in the elderly rocuronium and vecuronium groups, respectively, and 0.89 and 0.90 in the young rocuronium and vecuronium groups, respectively. Dynamic spirometry revealed decreases in forced expiratory volume in 1 s and forced vital capacity in both groups, and no significant changes in peak expiratory flow rate. The expiratory reserve volume was reduced more in the elderly groups. Oxygen saturation decreased in both groups. We conclude that oxygen saturation, pulmonary function, and muscle strength decrease more in the elderly than in their younger counterparts from priming doses of vecuronium or rocuronium. IMPLICATIONS: The priming principle consists of giving a subparalyzing dose of muscle relaxant 3-6 min before giving a second dose for tracheal intubation. We found that priming doses of vecuronium and rocuronium produced greater decreases in oxygen saturation and pulmonary function in the elderly (aged 65-73 yr) than their younger (aged 25-35 yr) counterparts. Priming may not be a safe approach in elderly patients.

[Acid base changes and muscle relaxants].

Previous publications have provided conflicting results concerning the effects of respiratory and metabolic acid base changes on the neuromuscular effects of nondepolarizing muscle relaxants. The varying results can be attributed not only to experimental design or species difference, but also to the accompanying changes in the pharmacokinetics in vivo. Using the phrenic nerve-hemidiaphragm preparation of rats, in which many variables of in vivo studies can be eliminated, respiratory and metabolic acid-base changes were induced by varying carbon dioxide (PCO2) and bicarbonate (HCO3) concentrations in the Krebs' solution and their effects on the potencies of muscle relaxants were compared. Decreasing pH by increasing Pco2 or by decreasing HCO3 increased the potencies of the monoquaternary relaxants (d-tubocurarine, vecuronium and rocuronium), while pH changes did not affect the potencies of the bisquaternary relaxants (metocurine, pancuronium and pipecuronium). Above difference between mono- and bisquaternary relaxants may reflect pH-induced changes in the ionization of the tertiary ammonium and resulting in changes in the sensitivity to the anionic nicotinic receptors. Neostigmine-induced antagonism was not affected by acid-base changes. These results in vitro were compared and correlated with the previous results in vivo.

The effect of isoflurane and temperature on the actions of muscle relaxants in rat in vitro.

Hypothermia and isoflurane alone increase the potencies of steroidal muscle relaxants (MRs). We studied the combined influence of isoflurane and hypothermia on MR potency. Phrenic nerve-hemidiaphragm preparations of rats were mounted in modified Krebs' solution and aerated with 5% CO2-95% O2 gas mixture at 37 degrees C and 4% CO2 at 27 degrees C to maintain the CO2 content constant. Phrenic nerves were stimulated with 0.1 Hz supramaximal impulses and elicited tension of the diaphragm was recorded. Isoflurane 1% was added after stabilization of twitch tension and MR was added 60 min later. Twitch tension was reduced by 20% +/- 2.5% at 37 degrees C and 3.5% +/- 0.7% at 27 degrees C from control with only isoflurane. The IC50 (inhibitory concentration, 50%) values of the MRs decreased significantly (P < 0.05) with isoflurane at both temperatures. The ratios of the IC50 values without and with isoflurane of the benzylisoquinolinium MRs were significantly more at both temperatures (P < 0.05) indicating the enhancement of potentiation of their action by isoflurane over steroidal MRs. When the soluble concentration of isoflurane at 27 degrees C was kept similar to that of at 37 degrees C, the ratios of all the MRs were reduced significantly from the ratios at 37 degrees C, indicating a reduction of potentiation. When the partial pressure of isoflurane was kept constant at 37 degrees C and 27 degrees C, the potentiating action of the MRs by isoflurane was similar. But when the partial pressure was decreased to keep the concentration of isoflurane constant, the potentiation was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypothermia on the in vitro potencies of neuromuscular blocking agents and on their antagonism by neostigmine.

The effect of temperature on the potencies of neuromuscular blocking agents remains unclear. This study was undertaken to examine the effects of different neuromuscular blocking agents at 37 and 27 degrees C at a constant carbon dioxide content (alpha stat principle). The effect of neostigmine 1 mumol litre-1 induced antagonism of these agents was also investigated. Phrenic nerve-hemidiaphragm preparations of rats were mounted in modified Krebs solution, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture, and at 27 degrees C with 4% carbon dioxide to maintain the carbon dioxide content of the solution constant. Phrenic nerves were stimulated with 0.1-Hz supra-maximal impulses of 0.2-ms duration and the elicited tension of the diaphragm recorded. The potencies of the steroidal neuromuscular blocking agents (rocuronium, vecuronium, pancuronium and pipecuronium) increased significantly at 27 degrees C (P < 0.05), while the potencies of the benzylisoquinolinium agents (tubocurarine and dimethyltubocurarine) did not change. Neostigmine-induced antagonism of the steroidal agents did not differ significantly between each other but differed significantly from the benzylisoquinolinium agents (P < 0.05) at both temperatures. The ratios of IC50 (inhibitory concentration, 50%) with and without neostigmine at hypothermia were slightly higher for the steroidal agents, indicating slight enhancement of antagonism by neostigmine at 27 degrees C. In contrast, the ratios were significantly greater at 27 degrees C (P < 0.05) for isoquinolinium agents, implying significant enhancement of antagonism. Our results indicate that at 27 degrees C the potency of all steroidal agents increased and neostigmine-induced antagonism was slightly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of CO2-induced acid-base changes on the potencies of muscle relaxants and antagonism of neuromuscular block by neostigmine in rat in vitro.

We investigated the influence of CO2-induced acid-base changes on the potencies of the monoquaternary relaxants (rocuronium, vecuronium, and d-tubocurarine) and bisquaternary relaxants (pancuronium, pipecuronium, and metocurine), and on the antagonism of their neuromuscular block by neostigmine. Phrenic nerve-hemidiaphragm preparations of rats were used. The pH changes were induced by changing the CO2 concentration aerating the modified Krebs solution. The potencies of the monoquaternary relaxants increased at 9% CO2 (pH 7.2) and decreased at 2.5% CO2 (pH 7.6) from those of 5% CO2 (pH 7.4) both with and without neostigmine (P < 0.05), whereas the potencies of the bisquaternary drugs did not change significantly at different pH levels from control (pH 7.4) both with and without neostigmine. The slopes of the log concentration-percent response curves of each drug were not significantly different at each pH level. The ratios of inhibitory concentrations, 50% (IC50) values with and without neostigmine at each pH value for each drug were not significantly different indicating that the neostigmine-induced antagonism for each drug was not affected by the CO2-induced acid-base changes. But the ratios of the IC50 values of the steroidal relaxants (rocuronium, vecuronium, pancuronium, and pipecuronium) were significantly lower (P < 0.05) than those of the isoquinolinium drugs (d-tubocurarine and metocurine) at each pH level, suggesting that the antagonism is enhanced at each pH level for the isoquinolinium relaxants. The difference was independent of their monoquaternary or bisquaternary nature. These results suggest that CO2 increases the potency of the monoquaternary relaxants but does not affect the bisquaternary relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketamine infusion for postoperative analgesia: a prospective cohort study in asthmatics.

Ketamine, most often used as an anaesthetic agent can provide adequate post operative analgesia when delivered in the form of infusion, replacing narcotics, which can cause bronchospasm in susceptible individuals. This cohort study was undertaken to assess the feasibility of providing complete post operative analgesia in asthmatics with ketamine delivered in sub-anaesthetic doses (6.10-6.41 ugm./kg.-1/min-1). Diazepam (0.97-1.02 ugm./kg.-1/min-1) was delivered from the same infusion to eliminate the unwanted effects of ketamine. Ketamine induced little alteration in blood pressure while tachycardia was significant (P < 0.05). Respiratory functions observed, were favourable for asthmatics. Diazepam helped in reducing ketamine induced side effects, but after infusion over long periods tendency of cumulation was observed. Complications encountered were minimum with more than 93% patient acceptability for this method of analgesia.

Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine.

Narcotics commonly used for postoperative analgesia may release histamine and cause bronchospasm in asthmatics. Ketamine, on the other hand, provides analgesia and has the additional advantage of preventing and relieving bronchospasm. We therefore delivered subanesthetic doses of ketamine in combination with midazolam (5.88-6.42 micrograms.kg-1.min-1 and 1.17-1.28 micrograms.kg-1.min-1, respectively), via an infusion for postoperative analgesia after elective abdominal hysterectomy in patients with asthma. Data were compared with those from a similar group of patients receiving conventional intramuscular meperidine. A significant degree and earlier onset of analgesia (P < 0.05) was achieved in the ketamine group. For other variables no significant difference was observed between the groups (P > 0.05). Ketamine-midazolam infusion can thus provide a safe alternative to the usual parenteral narcotic therapy in asthmatics, in terms of analgesia and patient acceptability.

Splenic salvage using an absorbable mesh: feasibility, reliability and safety.

Forty-nine adults underwent surgery for splenic injury: 17 (group 1) had salvage with a splenic mesh, seven (group 2) underwent other preservation techniques, and 25 (group 3) underwent splenectomy. There were six, zero and 11 hilar lesions in groups 1, 2 and 3, respectively. Seven of 15 associated lesions involved the digestive tract. There was no significant difference in transfusion requirements, length of operation or postoperative complications. One patient died in each of groups 1 and 2, and eight in group 3. Secondary splenectomy was performed once in groups 1 and 2. The duration of hospital stay was shorter in the preservation groups (1 and 2) than in group 3. Splenic preservation was feasible in 24 of 49 adults with splenic injury requiring surgery. The splenic mesh wrap is safe and reliable, and allows splenic salvage even with hilar injury.

Non typical presentation of systemic lupus erythematosis.

A case of systemic lupus erythematosis (SLE) affecting the heart, joints, skin and kidneys is reported. Antinuclear antibodies were insignificant at presentation. Diagnosis was only possible with passage of time and renal biopsy.

A study into loss of consciousness.

The case notes of patients admitted with loss of consciousness (LOC) to BMH Rinteln over 18 months were retrospectively studied. Forty percent of those diagnosed as epileptic were heavy goods vehicle (HGV) drivers. This paper audits the criteria for diagnosis and discusses its implications on the soldier's career.

Danazol-induced hypercalcaemia in alphacalcidol-treated hypoparathyroidism.

We report a case of idiopathic hypoparathyroidism, maintained on alphacalcidol who developed hypercalcaemia during treatment with danazol for endometriosis.