Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Reducing g(2)(0) of a parametric down-conversion source via photon-number resolution with superconducting nanowire detectors.

Multiphoton contributions pose a significant challenge for the realisation of heralded single-photon sources (HSPS) based on nonlinear processes. In this work, we improve the quality of single photons generated in this way by harnessing the photon-number resolving (PNR) capabilities of commercial superconducting nanowire single-photon detectors (SNSPDs). We report a 13 ± 0.4% reduction of g(2)(τ = 0), even with a collection efficiency in the photon source of only 29.6%. Our work demonstrates the first application of the PNR capabilities of SNSPDs and shows improvement in the quality of an HSPS with widely available technology.

Measuring the Joint Spectral Mode of Photon Pairs Using Intensity Interferometry.

The ability to manipulate and measure the time-frequency structure of quantum light is useful for information processing and metrology. Measuring this structure is also important when developing quantum light sources with high modal purity that can interfere with other independent sources. Here, we present and experimentally demonstrate a scheme based on intensity interferometry to measure the joint spectral mode of photon pairs produced by spontaneous parametric down-conversion. We observe correlations in the spectral phase of the photons due to chirp in the pump. We show that our scheme can be combined with stimulated emission tomography to quickly measure their mode using bright classical light. Our scheme does not require phase stability, nonlinearities, or spectral shaping and thus is an experimentally simple way of measuring the modal structure of quantum light.

Single-shot discrimination of coherent states beyond the standard quantum limit.

The discrimination of coherent states is a key task in optical communication and quantum key distribution protocols. In this work, we use a photon-number-resolving detector, the transition-edge sensor, to discriminate binary-phase-shifted coherent states at a telecom wavelength. Owing to its dynamic range and high efficiency, we achieve a bit error probability that unconditionally exceeds the standard quantum limit (SQL) by up to 7.7 dB. The improvement to the SQL persists for signals containing up to approximately seven photons on average and is achieved in a single shot (i.e., without measurement feedback), thus making our approach compatible with larger bandwidths.

Inlay osmotic pump tablets containing metformin and glipizide.

The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. A newly developed inlay osmotic pump tablet (IOPT) can deliver glipizide (GLZ) and metformin HCl (MET) gradually in controlled manner. The aim of present investigation was to prepare the IOPT that can deliver >75% of GLZ in 2 h, whereas MET released after 2 h and sustained up to 12 h. In the present work, HP-ß-CD was used to modify the solubility of GLZ before incorporating in the osmotic system and MET was spray-dried with HPMC A15C to modify its release profile, flow property, and compressibility. Various parameters mainly G(75%) (75% GLZ release), t(LMET) (lag time of MET release from device), Q(10 h) (percent of MET released within 10 h), and RSQ(ZERO) (R(2) of release data fitted to zero-order equation) were used to compare different formulations. The effects of different formulation variables, that is, osmagents, concentration of hydrophilic polymer, diameter of drug releasing orifice, and coating composition on the drug release profile were investigated. The release rate of GLZ could be effectively modified by the addition of sodium carbonate and sodium chloride, whereas the release rate of MET was adjusted by dual-coating system and by addition of hydrophilic polymer. The developed inlay osmotic system could be effective in the multidrug therapy of diabetes by delivering both drugs in a controlled manner.

Quantum-enhanced interferometry with large heralded photon-number states.

Quantum phenomena such as entanglement can improve fundamental limits on the sensitivity of a measurement probe. In optical interferometry, a probe consisting of N entangled photons provides up to a N enhancement in phase sensitivity compared to a classical probe of the same energy. Here, we employ high-gain parametric down-conversion sources and photon-number-resolving detectors to perform interferometry with heralded quantum probes of sizes up to N = 8 (i.e. measuring up to 16-photon coincidences). Our probes are created by injecting heralded photon-number states into an interferometer, and in principle provide quantum-enhanced phase sensitivity even in the presence of significant optical loss. Our work paves the way towards quantum-enhanced interferometry using large entangled photonic states.

Reduction in oral penicillamine absorption by food, antacid, and ferrous sulfate.

Plasma levels of penicillamine, urinary recovery of penicillamine and its oxidized metabolites, and urinary excretion of copper were examined after single 500-mg oral doses of penicillamine to six healthy men. Penicillamine was given after an overnight fast, a standard breakfast, and after antacid and ferrous sulfate. Following the fasting dose, the mean peak plasma level of 3.05 micrograms/ml developed at 3.8 hr and the drug was cleared from plasma with a t1/2 of 2.1 hr. Penicillamine levels were reduced to 52%, 35%, and 66% of those from the fasting dose after food, ferrous sulfate, and antacid. The rates of penicillamine appearance and disappearance from plasma were essentially treatment independent. There were good correlations between urinary recovery of total penicillamine (r = 0.875), between urinary copper excretion (r = 0.758) and the penicillamine plasma concentration AUCs. The availability of oral penicillamine is very susceptible to interactions with other substances. Further studies may be necessary to assess the full clinical significance of these interactions.

Visualization of suppressed thyroid tissue by technetium-99m-tertiary butyl isonitrile: an alternative to post-TSH stimulation scanning.

The autonomously functioning thyroid nodule (AFTN) is a discrete, nodular structure which operates independently of pituitary control and without relation to the remaining thyroid tissue. Presently, for the visualization of a suppressed thyroid lobe, a patient has to undergo the thyrotropin (TSH) stimulation test, which has several disadvantages. In this study we have used tertiary butyl isonitrile (99mTc-TBI), well known as a myocardial imaging agent, for visualization of the suppressed lobe. Thirteen of fourteen patients studied demonstrated a contralateral lobe on a 99mTc-TBI scan which was not visualized with a 99mTc0(4) or 131I scan. Although it is not possible to demonstrate the autonomous nature of the hyperfunctioning thyroid nodule using 99mTc-TBI, we conclude that it is feasible to use this agent to visualize the lobe without the TSH test.

Osseous pseudotumor. The sole manifestation of sinus histiocytosis with massive lymphadenopathy.

Sinus histiocytosis with massive lymphadenopathy may involve extra-nodal tissue sites. Skeletal involvement is uncommon and has always been associated with disease in other nonosseous locations. The present case is the first to document sinus histiocytosis with massive lymphadenopathy arising primarily within bone and unaccompanied by disease elsewhere.

Leuprolide acetate in the management of ureteral obstruction caused by endometriosis.

Endometriotic ureteral obstruction is a serious event commonly diagnosed late and therefore associated with a major risk of hydronephrotic renal atrophy. The standard therapy is surgical. However, medical treatment has been reported using danazol, progestins, and estrogen-progestin combinations, although solid documentation of the effect of hormonal therapy against ureteral endometriosis is lacking. Gonadotropin-releasing hormone (GnRH) agonist treatment of endometriosis has yielded good results but has not been adequately reported in patients with ureteric involvement. We report three patients treated with a GnRH agonist, leuprolide acetate, for 6-9 months as a preoperative course. One patient had bilateral and two had unilateral obstruction. The preoperative course relieved the obstruction in the patient with bilateral disease and in one with unilateral changes. The failure occurred in a patient with intrinsic ureteric endometriosis. This early experience suggests a place for GnRH agonist therapy for patients with ureteric obstruction due to endometriosis, probably, but not necessarily, in conjunction with a planned surgical procedure. If medical therapy is attempted, close surveillance of renal function is mandatory.

Leuprolide acetate in the management of cesarean scar endometriosis.

BACKGROUND: Progestin or estrogen-progestin combination therapy has not proven useful in the treatment of endometriosis of the abdominal scar after cesarean delivery. We report our experience in managing this condition with a gonadotropin agonist. CASE: A 22-year-old black woman with a history of two previous cesareans developed endometriosis of the abdominal scar. The extent of the lesion was estimated by computed tomographic (CT) scan, and a 6-month preoperative course of leuprolide acetate was administered. The patient exhibited prompt symptomatic response to the gonadotropin agonist, but the physical examination and CT scan findings were unchanged. Pathologic examination after surgical removal of the lesion confirmed the clinical diagnosis. CONCLUSION: Leuprolide acetate administered to a patient with cesarean scar endometriosis was associated with an improvement in symptoms, but there was no change in lesion size.

High-pressure liquid chromatographic determination of promethazine plasma levels in the dog after oral, intramuscular, and intravenous dosage.

Plasma levels of promethazine were determined using a high-pressure liquid chromatographic procedure incorporating a fixed wavelength (254 nm) UV detector, following single 50-mg intravenous, intramuscular, and oral doses to two male dogs. Initial plasma promethazine concentrations following intravenous doses were 556 and 535 ng/ml in the two dogs. The subsequent decline in drug levels were satisfactorily described by a triexponential function. Peak promethazine levels of 76 and 64 ng/ml were obtained 0.5 hr following intramuscular doses. Peak levels for the oral doses were 10.6 and 11.0 ng/ml occurring 2 hr after dosing. The apparent biological half-life of promethazine, obtained from only 2-3 data points, varied from 8.5 to 27.7 hr. Areas under the promethazine plasma curves, compared to values obtained from intravenous doses between 0 and 24 hr, indicated that systemic availability of intact drug was 55-73% following intramuscular injection and 8.3-9.5% following oral administration.

Pharmacokinetics of gentamicin in rabbits pretreated with nonsteroidal anti-inflammatory drugs: an interaction study.

Interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs occurs relatively frequently because of the wide use of NSAIDs. Such interactions with drugs of narrow therapeutic index used in serious disease states may lead to toxicity. Gentamicin toxicity is based on its concentration in serum, and any alteration in pharmacokinetic parameters may lead to gentamicin accumulation in the body and subsequently to severe nephrotoxicity and ototoxicity. To test this hypothesis, the effect of pretreatment with NSAIDs on gentamicin pharmacokinetics was examined in rabbit. Gentamicin sulfate (5 mg/kg) was administered to rabbits pretreated with aspirin (300 mg/kg), ketorolac tromethamine (3 mg/kg), ibuprofen (20 mg/kg), and piroxicam (2 mg/kg) twice a day for 1 week. The pretreatment with NSAIDs had significant effects on the body clearance and maximum concentration. Aspirin, piroxicam and ketorolac tromethamine pretreatment had significant effects on the area under the curve of gentamicin versus time. Aspirin and ketorolac tromethamine pretreatment had significant effects on the half-life of gentamicin. Aspirin had a significant effect on the volume of distribution of gentamicin. These results suggest that pretreatment with NSAIDs alters the pharmacokinetics of gentamicin and leads to accumulation inside the body, which could result in toxicity.

Bioavailability of hydrochlorothiazide from tablets and suspensions.

The bioavailability of hydrochlorothiazide was determined following single oral 25-, 50-, 100-, and 200-mg tablet and suspension doses in 12 healthy male volunteers. Plasma and urine levels of hydrochlorothiazide were determined by HPLC. Plasma levels of hydrochlorothiazide were satisfactorily described by a triexponential function. Mean peak plasma levels, Cmax (127-135, 270-280, and 437-490 ng/mL from the 25-, 50-, and 100-mg doses, respectively) were dose proportional, as were areas under plasma profiles, AUC0----36. Mean percentage recovery of unchanged hydrochlorothiazide in 48-h urine samples accounted for 50-59, 54-55, 60-63, and 54-57% of the 25-, 50-, 100-, and 200-mg doses, respectively. There were no significant differences among these values. Correlation coefficients between 48-h urinary recovery of hydrochlorothiazide and the plasma values (Cmax and AUC0----36) for the 25-, 50-, and 100-mg doses were 0.73 and 0.84. There were no differences in the net increases in electrolyte excretion among the treatments during the 0-12-h postdose period. The systematic availability of hydrochlorothiazide, unlike that of chlorothiazide, is dose proportional in the therapeutic range.

Bioavailability of tolazamide from tablets: comparison of in vitro and in vivo results.

The relative bioavailability of tolazamide was determined, in healthy male volunteers, from four different tablet formulations manufactured by direct compaction or granulation processes and the results were compared with in vitro disintegration and dissolution values. Serum tolazamide levels were determined by a high-pressure liquid chromatographic method developed in this laboratory. Serum tolazamide levels from the formulation that gave rise to rapid absorption were described by one-compartment model kinetics with a mean absorption half-time of 1.0 hr and an elimination half-life of 4.6 hr. Peak serum levels occurred at 3.3 hr after drug administration. Marked differences were observed in drug bioavailability from the four tablets, and the mean cumulative relative fraction of dose absorbed was 1.0, 0.42, 0.75, and 0.91 from Formulations A, B, C, and D, respectively. The hypoglycemic effect was closely related to serum tolazamide levels. Disintegration times did not predict in vivo tolazamide bioavailability. Dissolution rates provided an approximate rank order correlation with in vivo absorption but failed to be predictive among formulations. Currently available in vitro tests do not accurately predict tolazamide in vivo bioavailability characteristics among different formulations and manufacturing processes but may be useful to ensure lot-to-lot uniformity in bioavailability for a given formulation and specific method of manufacture.

Bioavailability of hydrocortisone from commercial 20-mg tablets.

The relative bioavailability of hydrocortisone was determined from four different 20-mg tablet formulations and one suspension in 15 healthy male volunteers; results were compared with in vitro dissolution rates. Plasma levels of hydrocortisone were determined by a liquid chromatography method developed in this laboratory. Dissolution of the tablet formulations, using the official USP test, varied from 7.8 to 93.8% in 30 min. Similar plasma profiles were obtained from all tablet products, and there were no differences among tablets in the cumulative percentage of drug absorbed. There were no clear trends in any pharmacokinetic parameter values among the tablet dosages, and the four products were considered bioequivalent. The suspension dosage yielded significantly higher plasma levels compared with some of the tablet formulations during the initial 30-min postdose, significantly higher cumulative absorption at 0.5 and 1.0 h compared with one tablet formulation, and significantly higher ka and Cmax, and shorter tmax values, compared with some of the tablets.

Significance of MRI changes after surgery of the skull base.

Magnetic resonance (MR) imaging is commonly used in the followup of patients who have undergone surgical removal of tumors from the cranial base to assess the possibility of tumor recurrence, persistence, or surgical complications. Interpretations of this study must be cautious because postoperative enhanced signals are encountered frequently. Although technological improvements continue to enhance the usefulness of MR images for followup, problems remain in differentiating between fibrotic, reconstructive changes, and tumor recurrence. In this study, the hospital records and MR findings of 215 patients who had undergone skull base surgery were reviewed. The study was prompted by negative operative exploration in three patients in whom postoperative MR images strongly suggested tumor recurrence. One-year follow-up images were available in 174 patients. Of these, 94% showed signal enhancement on the 1-year follow-up study. Progressive changes were observed in 14% of patients. The correlation of preoperative MR findings and surgery, with regard to dural involvement, vascular involvement, cranial nerve infiltration, and extent of intracranial infiltration, was analyzed in 28 patients. Methods to facilitate the detection of tumor recurrence using MR images are reviewed.

Leuprolide acetate depot for the treatment of uterine leiomyomas. Changes in bone density, uterine volume and uterine vascular resistive index.

This study measured the changes in uterine volume, uterine vascular resistive index and lumbar vertebral bone density before and after a six-month course of leuprolide acetate depot in women with uterine leiomyomas. All nine patients studied were black. The high baseline bone density of black women may provide a greater scope for the use of gonadotropin agonists as compared to women in the general population. A significant reduction in uterine volume was achieved in the patients with leuprolide therapy. Uterine vascular resistive indices were not altered consistently following leuprolide therapy in women with leiomyomas.

Interstitial lymphoscintigraphy for diagnosis of lymphocele.

A patient with the development of a post-surgical mass in the thigh, at the site of surgery, is described. Lymphoscintigraphy was important in solving the clinical dilemma.

Animal model for liver dysfunction using lomustine in Wistar rats.

AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg body weight of CCNU were injected intraperitoneally in separate groups of animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels increased for up to 72 hours and then slowly returned to normal. With a dose of 20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase levels increased for 72 hours and then returned to normal over 4-5 weeks. With a dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day 17. Pathological studies were carried out after injection of 30 mg/Kg body weight of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific inflammation and bile duct proliferation. After 16 days, triaditis was observed with deposition of collagen. Focal fibrosis was also noticed. There was no significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of hepatocytes separated by irregular fibrous bands indicated cirrhosis. CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using CCNU; this model may be used to assess the utility of hepatobiliary radiopharmaceuticals.