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We report a case of a 41-year-old male with anticipated difficult airway undergoing a repair of a bilateral radial fracture under bilateral sequential brachial plexus block. Anesthesiologists are reluctant to perform bilateral blocks because of the fear of complications like diaphragmatic paralysis, local anesthetic (LA) toxicity, and pneumothorax. We advise that with the correct application of LA pharmacokinetics, careful patient selection and usage of ultrasound, bilateral blocks can be done safely. We used chloroprocaine as an LA in one of the blocks to reduce the dose required for the more toxic LAs. chloroprocaine’s fast metabolism also helped us to prevent the overlapping of peak plasma concentration of different LAs. To our knowledge, this is the first reported case in the literature where chloroprocaine was used for bilateral brachial plexus block.

The determination of alendronate (ALE) in biofluids using a low-cost instrument is potentially useful in preclinical pharmacokinetic studies. This study developed and validated a high-performance liquid chromatography with ultraviolet method for ALE determination in rat plasma using precolumn derivatization with phenyl isothiocyanate (PITC). Inhibiting compounds in the samples were first eliminated using solid-phase extraction. ALE in the sample was subsequently allowed to react with PITC to form a phenylthiocarbamoyl derivative for further analysis. The assay was linear within the concentration range of 0.29–25.0 µg/mL. The precision and accuracy were less than 3.9% and 98.0 ± 3.9%, respectively. The limits of detection and quantification were 0.08 and 0.20 µg/mL, respectively. The method was successfully used to evaluate the pharmacokinetic parameters of ALE in rats following a single oral administration (30.0 mg/kg). The results show that the peak plasma ALE concentration is 0.69 ± 0.18 µg/mL. ...

To determine the plasma disposition of meloxicam in goats following S/C, oral or I/V administration at a single dose of 0.5 mg/kg bodyweight.Five healthy Saanen goats, aged 12-14 months and weighing 35-40 kg, were used for a three phase cross-over design with a 10-day washout period, with meloxicam administered I/V, then orally and S/C. Heparinised blood samples (5 mL) were collected from all animals prior to drug administration (0 hours) and subsequently up to 96 hours. Concentrations of meloxicam in plasma were measured using high performance liquid chromatography. Concentration-time curves were fitted and pharmacokinetic parameters were estimated for each administration group.Subcutaneous administration of meloxicam exhibited unique plasma distribution characteristics that differed from oral and I/V administration. Mean peak plasma concentrations were greater (1.91 (SD 0.39) vs. 0.71 (SD 0.17) µg/mL) and the time to reach them shorter (3.20 (SD 1.64) vs. 14.33 (SD 2.19) hours) following S/C compared with oral administration (p0.05). The terminal half-life was longer (15.16 (SD 4.74) vs. 10.69 (SD 1.49) hours) and the MRT was shorter (15.67 (SD 2.37) vs. 24.33 (SD 3.12) hours) following S/C than oral administration (p0.05), but bioavailability was similar (98.24 (SD 9.62) vs. 96.49 (SD 10.71)%).Subcutaneous administration of meloxicam resulted in long-term presence of drug at high concentration in goat plasma. This unique plasma disposition characteristic may offer an advantage in some clinical cases towards potentially improving the treatment efficacy in goats.

The present study was expected to develop colon-specific guar gum compression coated tablets of ketorolac tromethamine (KTM). In this study, the core and compression coated tablets were prepared by direct compression method and evaluated. Samples obtained from in vitro dissolution and in vivo pharmacokinetic studies were analyzed using the HPLC method at 319 nm using UV detector. From the in vitro dissolution studies, the formulation F4 showed 4.92±0.36 % drug release in 5 h and it was progressively expanded to 99.92±0.68 % in 24 h. From the pharmacokinetic evaluation, the immediate release tablets producing peak plasma concentration (Cmax) was 4524.61 ng/ml at 2 h Tmax and colon targeted tablets demonstrated Cmax=3396.83 ng/ml at 10 h Tmax. The area under the plasma KTM concentration versus time curves for the immediate release and compression coated tablets were 10894.67 and 17647.58 ng-h/ml respectively and the mean resident time was 3.92 and 10.25 h respectively. From the above results, colon ...

Multiple sclerosis is a progressive demyelinating neurological disease resulting in long-term disability, commonly manifesting in walking impairment and reduced quality of life. The use of the potassium channel blocker fampridine, chemically 4-aminopyridine, as an immediate-release formulation to improve action potential conduction in demyelinated axons was hampered by adverse events, including seizures. The prolonged-release formulation of fampridine (known as modified- or sustained-release fampridine in some countries and dalfampridine extended release in the USA) has a longer apparent half-life and a lower peak plasma concentration versus immediate-release fampridine formulations, sustaining its duration of action and reducing the incidence of adverse events. Prolonged-release fampridine is the first drug specifically licensed to improve walking in patients with multiple sclerosis, and has been shown to consistently improve walking ability in a third of patients. Prolonged-release fampridine Timed-Walk Responders showed both clinically significant improvements in walking speed and in patient-reported walking ability.

This clinical study investigated the pharmacokinetics of standard doses of rifampicin (RMP; 450 and 600 mg) in pulmonary tuberculosis (TB) patients in the context of its high sterilizing potential and the increased frequency of multidrug-resistant TB in Pakistan. The objective of this study was to determine the sufficiency or inadequacy of peak plasma levels of RMP in pulmonary TB patients after the administration of standard doses.Twenty adult patients with newly diagnosed pulmonary TB consented to participate in the study. Blood sampling for pharmacokinetic assessment of RMP was done after at least 14 days of regular daily treatment to ensure steady state. Plasma concentrations of RMP were determined by a validated high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection.The peak plasma concentration of RMP at 2 h was subtherapeutic, i.e. 3.76 ± 1.23 mg/l (range 1.80-6.62), in all of our patients. Out of 20 patients, 13 (65%), had 2-h plasma concentrations below 4 mg/l.This study reports evidence of suboptimal RMP concentrations in a small group of Pakistani TB patients and highlights the need for larger clinical studies to identify possible reasons and consequences of low RMP levels in terms of treatment outcomes. Quality control problems in local drug preparations used widely among TB patients in Pakistan need to be addressed as a matter of urgency.

1. The objective of this study was to investigate the effect of concomitantly administered silymarin on the pharmacokinetics of talinolol, a typical substrate for P-glycoprotein (P-gp), in healthy Chinese volunteers and its association with a multidrug resistance 1 (MDR1) C3435T genetic polymorphism. 2. Eighteen healthy adult men (six MDR1 3435CC homozygotes, six MDR1 3435CT heterozygotes and six MDR1 3435TT homozygotes) were recruited in a two-phase, randomized, single-blind, crossover design. The pharmacokinetics of talinolol were measured after co-administration of placebo or 140 mg silymarin capsules three times daily for 14 days. Concentrations of talinolol in plasma were measured for up to 36 h after drug administration by liquid chromatography-mass spectrometry (HPLC-MS). 3. The peak plasma concentration (C(max)) of talinolol was significantly higher after silymarin administration as compared with placebo (p = 0.007). The area under the plasma concentration-time curve from zero to 36 h (AUC(0-36)) and AUC(0-infinity) of talinolol was increased by 36.2% +/- 33.2% and 36.5% +/- 37.9%, respectively, by silymarin co-administration. The oral clearance (CL/F) of talinolol was decreased by 23.1% +/- 16.6% (p < 0.001) during the silymarin-treated phase. No change in the time to peak concentration (t(max)) and the blood elimination half-life (t(1/2)) of talinolol was observed between the placebo- and silymarin-treated phases. 4. Co-administration of silymarin significantly increased the plasma concentration of talinolol in healthy volunteers.

Several acute toxicities in monkeys have been associated with administration of phosphorothioate oligonucleotides including effects on coagulation and complement cascades. These effects are transient in nature and the severity is closely associated with peak plasma concentrations of the oligonucleotide. Similar properties have been observed for several oligonucleotides with different base sequences.

The relative bioavailability of iron sulphate added to a soybean product intended for use as a fortified product for complementary feeding of infants was determined. Ten adults received 100mg elemental iron in an aqueous Fe(II)-sulphate solution and 1 week later 100 mg elemental iron mixed into 30 g soybean milk powder. Plasma iron concentrations were measured before, and 1, 2, 4, 6, 8 and 10 h after consumption. The area under the concentration/time curve (AUC+), the peak plasma level (tmax) and the relative bioavailability were determined. The peak of the plasma iron level after receiving 100 mg of iron solution was 176.71 ± 39.05 μg/dl at tmax = 2.8 ± 1.03h while it was 139.82 ± 34.47 μg/dl at tmax = 2.4 ± 1.3 h after consuming 30 g of soybean milk product mixed with 100mg iron solution. The relative bioavailability of iron in the soybean product was 45.8% compared to iron solution. Based on these results it is suggested that the soybean product should be fortified with 10 mg/100 g product of iron sulp...

Confidence limits associated with Chow and Shao's 90% joint confidence region method (CS CR limits) were derived to assess the bioequivalence (BE) of drug products. The CS CR method provides three conditions that must be simultaneously satisfied to conclude BE, which is applicable only for raw scale data. The CS CR limits method extends its applicability to both raw scale and log-transformed data. In addition, it is easy to interpret. The quantitative limits provide information, such as how much the test product deviates from the reference product in bioavailability. The data sets of peak plasma concentration (C(max)) and area under plasma concentration curve (AUC) of 13 BE studies involving 10 drugs were used to compare the performances of classic confidence interval (classic CI), CS CR, and CS CR limits methods. The results indicate that the same BE conclusion can be reached for CS CR and CS CR limits methods. The CS CR and its limits method offered a distinctive advantage in terms of percentage passing the BE criteria by taking account of the correlation and variability of sample means. Similar BE conclusion was observed for CS CR limits method by using raw and log-transformed data in this study.

The bioavailability of a generic preparation of metoprolol (Beatrolol®) was evaluated in comparison with a proprietary product (Betaloc®). Twelve healthy volunteers participated in the study conducted according to a two-way crossover desing. The bioavailability was compared using the parameters, total area under the plasma level-time curve (AUC0-00), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic tranformed AUC0-00 values of Beatrolol over those of Betaloc was found to lie between 0.93 and 1.07, which is within the acceptable equivalence limit of 0.80-1.25. From the data obtained, it also appeared that a relatively high proportion of our volunteers were poor metabolizers of metoprolol. The mean elimination half-life (t1/2), was found to be relatively larger than those report...

Sacral neuromodulation (SNM) is a minimally invasive therapy for defecatory disorders. PEAK Plasma Blade™ (Medtronic) has been used as an alternative to the conventional electric scalpel and scissors in 3 procedures of neuromodulation. PEAK PlasmaBlade™ uses less total energy, operating at significantly lower temperatures than electrosurgical technology. No damage to the wires or pulse generators or patient complications were detected during the surgery or follow-up. A reduction in the duration of the procedures was noted.

Male and female cynomolgus monkeys received whole-body inhalation exposures to dimethylformamide (DMF) at concentrations of 30, 100, and 500 ppm for 6 hours a day, 5 days a week over a 13-week period. Serial blood samples were drawn at the conclusion of the first day of exposure and following 15, 29, 57, and 85 days of testing. Area under the plasma concentration curve (AUC) values were determined for DMF and "NMF" [N-methylformamide (NMF) plus N-(hydroxymethyl)-N-methylformamide (DMF-OH)]. Urine samples were also collected and assayed for DMF, NMF and DMF-OH. The systemic exposure to DMF increased disproportionately as the airborne DMF concentrations increased. DMF AUC values increased 19- to 37-fold in male and 35- to 54-fold in female monkeys as the inhalation concentrations increased 5-fold (100 to 500 ppm). These data are consistent with saturation of DMF metabolism as inhaled DMF concentrations increased from 100 to 500 ppm. AUC values, peak plasma concentrations, and plasma half-lives were essentially unaltered over the duration of the study within each exposure concentration tested. Estimated plasma half-lives ranged from 1 to 2 hours and 4 to 15 hours for DMF and "NMF" respectively. DMF was rapidly converted to "NMF" following 30 ppm exposures, with "NMF" plasma concentrations higher than DMF plasma concentrations at the 0.5 hour time-point. In plasma samples simultaneously assayed for DMF-OH and NMF, the concentration of DMF-OH exceeded, was equal to, or was less than NMF concentrations depending upon the plasma sample. DMF-OH was always the main urinary metabolite (56 to 95 percent) regardless of exposure level or time on study.

Arthrotec, a combination tablet has been developed that contains 50 mg of diclofenac in an inner core and 200 micrograms of misoprostol in an outer mantle. Both diclofenac and misoprostol are extensively absorbed and their maximum plasma concentrations, but not total availability, are diminished when taken with food. Both drugs have elimination half-lives of less than 2 hours and do not accumulate in plasma after recommended doses. Pharmacokinetic and bioavailability studies of the combination product taken separately and together reveal a high between- and within-subject variability in plasma diclofenac levels, especially when the enteric-coated tablets were given after food; reliable values for peak plasma diclofenac concentration could not be ascertained. No pharmacokinetic interactions between diclofenac and misoprostol were apparent. The bioavailability of diclofenac and misoprostol from the combination tablet was similar to that seen when the two drugs are given separately.

1. The disposition of [14C]pranolium chloride, a dimethyl quaternary derivative of propranolol, has been studied in rats, mice and hamsters after oral or parenteral dosage.2. Elimination of 14C occurred largely via the kidneys after parenteral dosage, but biliary excretion was significant. Pranolium chloride was excreted unchanged and as a conjugate, and was also metabolized to 1-naphthol which was conjugated.3. The radiolabel was localized in the liver, kidneys, heart, lungs and gastro-intestinal tract of the rat, but did not pass the placental or blood-brain barriers to any appreciable extent. Unchanged pranolium chloride was localized in rat cardiac tissue for at least 6 h after i.v. dosage.4. Pranolium chloride was poorly and variably absorbed from the gastro-intestinal tract, of animals. Peak plasma levels occurred between 10 min and 1 h. The absorption of the pranolium cation was marginally increased after prolonged fasting, but was not affected by the presence of alternative anions.

Ampicillin was administered intramuscularly and amoxycillin or pivampicillin orally to 14 fasting newborn infants, 6-13 days old, in a cross-over trial. The dose was 50 mg/kg twice daily. The mean peak plasma level of amoxycillin and pivampicillin was 58% (range 35-96%) and 48% (33-82%) of that noted after i.m. ampicillin, which gave a value of about 44 +/- 5 micrograms/ml (mean +/- SEM) in both groups. The area under the time-concentration curve was 75% (range 60-101%) of that of i.m. ampicillin for amoxycillin and 51% (20-76%) for pivampicillin (p less than 0.05). Both drugs, especially amoxycillin, should be useful for oral treatment of neonatal infections caused by susceptible microorganisms in infants who are not critically ill.

1. After oral administration of the anti-lipolytic drug [14C]tizoprolique acid (2-propyl-5-carboxyl[4-14C]thiazole), to baboons (60 mg/kg), the radioactivity was well absorbed and rapidly excreted. During 6 and 24 h respectively, 60 +/- 25% (S.D.) and 90 +/- 2% were excreted in the urine. 2. Plasma concn. of 14C reached a max. (182 +/- 65, range 85-221 micrograms equiv./ml) at 1-1.5 h after an oral dose, and declined rapidly with an apparent half-life of about 0.5 h. A mean of 77 +/- 7% of the 14C in peak plasma samples was bound to plasma proteins, somewhat less than that of [14C]tizoprolique acid (84 +/- 5%). 3. Tissue concn. of 14 C were highest in an animal killed at 0.5 h after an oral dose, but were lower than those in plasma in all tissues examined except the kidneys. 4. The major metabolite of tizoprolique acid was its glycine conjugate, which accounted for about 80% dose excreted in the 24 h urine. About 2% dose was excreted as unchanged drug. About 70% and 20% respectively of plasma 14C were associated with the unchanged drug and its glycine conjugate during the period 15 min to 4 h after dosing.

The fate of silvex [2-(2,4,5-trichlorophenoxy)propionic acid] was defined in seven men and in one woman following oral administration of 1 mg/kg. No adverse effects were observed. Samples of blood plasma, urine, and feces were collected at designated time intervals through 168 hr. Plasma samples were analyzed for silvex only, while samples of urine and feces were analyzed for silvex, silvex conjugate(s), 2,4,5-trichlorophenol, and 2,4,5-trichlorophenol conjugate(s). Apparent first-order kinetics described the biphasic clearance of silvex from plasma and excretion in urine. The half-life values for clearance of silvex from plasma were 4.0 +/- 1.9 and 16.5 +/- 7.3 hr for the initial and terminal phases, respectively. Peak plasma levels of silvex occurred within 2-4 hr after dosage. Within 24 hr after administration, 65% of the administered dose had been excreted in urine. Silvex was excreted in urine as silvex and silvex conjugate(s). The half-life values for excretion of silvex per se in urine were 5.0 +/- 1.8 and 25.9 +/- 6.3 hr for the two phases, respectively. Small amounts (3.2% or less) of silvex and/or silvex conjugate(s) were eliminated in feces. Recovery of silvex and its conjugate(s) in urine and feces through 168 hr ranged from 66.6 to 95.1% of the administered dose, with a mean value and standard deviation of 80.3 +/- 10.5%. In humans, silvex is readily absorbed after ingestion and subsequently readily excreted, predominantly via the urine.

Flushing by ad libitum feeding following a period of restriction has resulted in improved litter size in mink. In this investigation effects of 4 different flushing models on plasma estradiol-17β, plasma progesterone, number of corpora lutea, implantation sites and litter size were studied. Flushing from March 4, preceded by moderate restriction, resulted in superior estimated numbers of corpora lutea and a tendency for increased number of implantation sites and litter size. Plasma estradiol-17β tended to increase from February 25 to March 8 but was not affected by the experimental treatment. Plasma progesterone levels started to increase 4.0–7.7 days before the estimated day of implantation (34.0–37.7 days before parturition). The interval between day of increase in plasma progesterone and recorded day of peak plasma progesterone was shorter in three of the flushed groups compared with the control group. The level of plasma progesterone was not affected by the experimental treatment, estimated n...

Plasma and erythrocyte concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Eleven children (9 with acute lymphatic leukemia) were studied after oral intake of 6-MP doses ranging between 31 and 128 mg/m2 body surface area. The concentrations of 6-MP in plasma were found to vary considerably between patients even after dose normalization to 75 mg/m2. After dose normalization the mean peak plasma concentration was 0.68 microM (range 0.12-1.38) and the area under the plasma concentration-time curve (AUC) was 1.37 microM.h (range 0.12-3.04). The mean time taken to reach the peak concentration was 1.3 h (range 1-2), and the half-life of elimination was 1.8 h (range 0.6-2.5). No patient had detectable 6-MP concentrations 12 h after dose intake. The concentrations of 6-MP tended to be higher in erythrocytes than in plasma. The mean peak concentration in erythrocytes was 131% and the AUC 145% of that found in plasma. The mean half-life of elimination from erythrocytes was 2.0 h (range 0.7-2.8). These data indicate that 6-MP can pass through all membranes rapidly to reach intracellular concentrations equal to or even higher than in plasma. In summary, marked interindividual differences in pharmacokinetics were found, probably due to highly variable bioavailability of oral 6-MP. Further studies are needed to determine whether measurements of plasma concentrations of 6-MP can be used to optimize maintenance treatment of childhood leukemia.

The relative bioavailabilities of a new once-a-day propranolol formulation (Duranol) and conventional propranolol tablets (Inderal) were evaluated in six healthy male volunteers in a randomized balanced cross-over study. During the first treatment period, subjects were administered either a single 160 mg Duranol capsule at 9 a.m. or 80 mg Inderal at 9 a.m. and 9 p.m. Plasma propranolol concentrations were measured at 0, 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 15, 16, 24 and 36 hours after the 9 a.m. dose.Mean peak plasma propranolol concentrations (Cmax) of 92.7 ng/ml at 2 hours and 53.9 ng/ml at 2.8 hours were recorded after administration of the first and second Inderal doses, respectively. After Duranol dosing, the Cmax of 85 ng/ml was not significantly different than the Inderal values; however, Duranol's tmax of 8 hours was significantly greater (p < 0.05) than either tmax recorded for Inderal. Compared to data obtained after administration of conventional propranolol tablets, mean propranolol conc...

1. The fate of [14C]rimiterol given orally, by aerosol, and intravenously to asthmatic patients has been investigated.2. Following oral dosage (10 mg) < 50% dose was excreted in the urine. Two peaks in plasma concn. were seen, at 1–2 h and 3–5 h after dosing. Plasma radioactivity due to free rimiterol varied but never exceeded 10%. Of the urine radioactivity 50.5% was excreted as rimiterol (free and sulphate ester), and 30.5% as 3-O-methyl rimiterol (free and sulphate ester); free rimiterol accounted for only 1.7% and free 3-O-methyl rimiterol 2.5% of dose.3. Following aerosol administration (0.39–0.56 mg) the pattern of metabolism and excretion was similar to that seen after oral administration.4. After intravenous infusion (0.038 and 0.216 mg over 10 min) 92% of dose was excreted in the urine, suggesting little biliary excretion. Peak plasma concn. were seen 2–4 min after the end of injection at which time most of the radioactivity was due to free rimiterol. Of the urine radioactivity, 28.45% was excret...