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PubMed1991

Determination of small drug molecules by capillary electrophoresis-atmospheric pressure ionization mass spectrometry.

Capillary electrophoresis (CE) separations are reported for sulfonamides and benzodiazepines in an uncoated fused-silica capillary. The capillary column exit was connected to a liquid junction-ion spray interface combination coupled to an atmospheric pressure ionization (API) triple quadrupole mass spectrometric (MS) system. On-line UV detection occurred 20 cm from the inlet of the capillary and with the API mass spectrometer (CE-API-MS) after the entire length of the capillary (100 cm). The separations were made using volatile buffers composed of ammonium acetate (15-20 mM) with 15-20% of methanol to facilitate ionization under electrospray conditions. This study showed that the major metabolite of flurazepam in man, N-1-hydroxyethylflurazepam, could be detected and characterized in human urine by CE-UV-MS following the administration of a single oral dose of 30 mg of flurazepam dihydrochloride. The presence of additional flurazepam metabolites in human urine was observed by using the system, suggesting that a combination of UV with MS detection should be useful for metabolic studies. In addition to molecular weight determination of compounds, structural information may be obtained by utilizing online tandem mass spectrometry (CE-UV-MS-MS). This was demonstrated for sulfamethazine where the protonated molecule species was transmitted into the collision cell of the tandem triple quadrupole mass spectrometer. Collision-induced dissociation of the protonated sulfamethazine molecule yielded structural information characteristic of the sulfa drug following the on-column injection of 2 pmol of sulfamethazine.

Benzodiazepines↗
PubMed1994

Cholinergic drug interactions and heat tolerance.

Acute, subchronic and chronic exposures to cholinergic compounds may result in differing effects. The efficacy of pyridostigmine bromide (PY) prophylaxis against organophosphorus poisoning depends on post exposure atropine (AT) administration. AT induces a dose-dependent increase in rate of rise of core temperature in heat exposed humans and rats. To determine whether AT's anticholinergic potency is altered following PY administration, we examined AT's effects following acute or subchronic (2 weeks) PY administration in the sedentary heat-stressed rat. Four groups of rats were acutely (a, i.v.) treated with saline (SAL) or PY (100 ug/kg) followed by SAL or AT (200 ug/kg), and 4 groups were subchronically (c, osmotic pump) treated with SAL or PY (20 ug/hr) followed by SAL or AT (200 ug/kg). Fifteen minutes following the final injection, rats were subjected to an ambient temperature of 41.5 degrees C until a core temperature of 42.6 degrees C was attained. Heat tolerance times were significantly improved for cPY+SAL over aPY+SAL (241 +/- 9 vs 187 +/- 16 min, mean +/- SE) and for cPY+AT over aPY+AT (76 +/- 9 vs 57 +/- 2 min). The improvement in thermoregulation resulted from increased salivary water for evaporative cooling indicated by % weight loss (corrected for fecal loss) during heat stress: cPY+SAL over aPY+SAL (8.4 +/- 0.3 vs 6.6 +/- 0.5%). This increased heat tolerance resulting from subchronic anticholinesterase administration resembles changes seen with heat acclimation.

Analysis of Variance↗
PubMed1987

Measurement of lactate-induced panic and anxiety.

Acute Panic Inventory (API) scores were obtained from 26 normal controls and 89 patients with either panic disorder or agoraphobia with panic attacks before and during lactate infusions. Retrospective ratings of the patients' usual spontaneous attacks were much higher, by API, than ratings of moments of severe stress by the controls. Point of panic API scores, as well as increments of panic scores over prelactate scores, were higher for patients who experienced lactate panics than for both controls and patients who did not panic.

Adult↗
PubMed1987

Antipanic drug effects during lactate infusion in lactate-refractory panic patients.

In previous articles we have reported on the total Acute Panic Inventory (API) score during lactate-induced panic. Even patients with panic disorder who do not panic during lactate infusion have higher API scores during the infusion than normal controls. In this post hoc analysis, we wished to determine whether specific API items were more sensitive to the beneficial effects of antipanic medication, either at baseline or during the infusion, in these lactate-insensitive panic patients. Four of the 17 items showed specific drug blockade of baseline severity. Five additional items showed specific drug blockade of lactate exacerbation of symptom severity. Medication apparently had no effect on severity of the remaining eight items. We suggest that the nine symptoms that responded to drug therapy are associated with hyperventilation. The study indicates that antipanic drugs may have a specific effect in blunting hyperventilation.

Adult↗
PubMed1995

Effects of intravenous diazepam pretreatment on lactate-induced panic.

The psychological and physiological effects of acute low-potency benzodiazepine administration on lactate-induced panic were examined in 10 patients with panic disorder (PD). The patients, who had panicked during a standard sodium-lactate infusion, underwent a repeat infusion modified by pretreatment with intravenous diazepam (5 mg). Acute Panic Inventory (API) scores preceding the second lactate infusion, which were associated with diazepam pretreatment, were significantly reduced in compared with those measured before the first lactate infusion. However, the second visit "fear of doom" item of the API was significantly reduced relative to the same time point of the first visit 35 min before lactate infusion, when diazepam had not yet been administered. Thus, the reduction of prelactate anxiety preceding the second infusion appeared to reflect both pharmacological and nonpharmacological contributions. The diazepam pretreatment condition was associated with a significantly increased infusion duration and a significant attenuation of rate of API symptom increase in response to lactate. Despite significant attenuation of lactate infusion effects associated with the diazepam pretreatment condition, 7 of 10 patients experienced a second panic attack. This pilot study suggests that diazepam pretreatment is associated with a marked reduction of symptomatic response during a second lactate infusion, although the magnitude of attenuation observed was insufficient to block lactate-induced panic in a majority of lactate-vulnerable PD patients.

Adult↗
PubMedDate not supplied

Early changes produced in mouse skin by the application of three middle distillates.

It has been reported by the American Petroleum Institute (API) that dermal applications of certain middle distillates of mineral oils can result in high incidences of skin tumours in mice. This was unexpected as the polycyclic aromatic hydrocarbon (PAH) levels in these were below detection limits. To examine the possible role of tissue injury in the induction of tumours, the skin reactions produced by thrice weekly applications of three middle distillates similar to those tested by the API were examined grossly and histopathologically at intervals up to 6 weeks. Various reference materials and oils were used as controls. Preliminary histological examination showed that severe skin damage was present from week 1 onwards in mice treated with the three middle distillates, two of them producing epidermal loss and ulceration. Marked epidermal hyperplasia was produced by all three middle distillates. These findings support the view that regenerative epidermal hyperplasia due to repeated severe skin damage may have exerted a powerful promotional effect in the production of the skin tumours by middle distillates in the API study.

Animals↗
PubMedDate not supplied

Recent developments in electrospray mass spectrometry including implementation on an ion trap.

Mass spectrometry (MS) may be the ultimate detection technique when combined with modern condensed phase separation sciences. The technique combines sensitivity with excellent specificity, so the pharmaceutical analyst can obtain definitive information regarding components separated in a mixture. Thus, mass spectrometric detection not only provides evidence of a chromatographic peak, but it also provides important information including molecular weight and structural information enabling identification of the components. The coupling of an atmospheric pressure ionization (API) mass spectrometer to most of the separation science techniques offers a simpler alternative from earlier non-routine, less sensitive systems where the vacuum systems struggled to handle the liquid effluent from these systems. Contemporary sensitive and analytically rugged API systems can be operated unattended for extended periods of time thus reducing the cost per sample to a reasonable value especially given the wealth of information provided. Although the mass spectrometer is more complicated than conventional spectroscopic detectors, present day API systems effectively decouple the liquid-phase separation inlet from the high-vacuum system where mass analysis occurs. The ability to form gas-phase ions at atmospheric pressure and sample primarily the analyte ions into the mass spectrometer promises a bright future for combining on-line condensed phase separation science techniques with mass spectrometry. The increasing ease of performing these experiments offers new analytical opportunities for pharmaceutical laboratories.

Carbohydrate Sequence↗
PubMed1986

Susceptibility testing of methicillin-resistant Staphylococcus aureus with three commercial microdilution systems.

The antimicrobial susceptibilities of 100 methicillin-resistant Staphylococcus aureus isolates were determined concurrently by API Uniscept KB, Micro-Media, MicroScan, standardized disk diffusion, and reference broth microdilution to evaluate whether these commercial microdilution systems would reliably defect methicillin-resistant S. aureus. The methicillin minimal inhibitory concentration for all isolates was greater than or equal to 16 micrograms/ml as determined by the reference minimal inhibitory concentration panels containing 2% NaCl supplemented Mueller-Hinton broth. Using the breakpoints established by the National Committee for Clinical Laboratory Standards for reporting susceptible and resistant methicillin results, there was 100% agreement between the reference methods and API Uniscept KB at 24 hr. The Micro-Media and MicroScan systems had 47% and 8% very major discrepancies at 24 hr, respectively. At 48 hr, these two systems exhibited 15% and 0% very major discrepancies. Micro-Media and MicroScan were in agreement with the reference microdilution method (+/- 1 log2 dilution) for 62% and 68% of the strains at 24 hr, respectively and 88% and 85% of the isolates at 48 hr, respectively. The results of this study indicate that API Uniscept KB would provide a practical and reliable method for the detection of methicillin-resistant S. aureus.

Anti-Bacterial Agents↗
PubMed1996

Symptoms essential to the experience of sodium lactate-induced panic.

We report on subjective ratings and symptoms experienced before and during sodium lactate infusion by patients with panic disorder or agoraphobics with panic attack (DMS-III-R criteria). Symptoms were assessed using the Acute Panic Inventory (API). During the lactate infusion 59% of the patients were rated by an attending psychiatrist as having experienced lactate-induced panic attacks. Patients experiencing lactate-induced panic attacks overwhelmingly rated this experience as very similar to their typical naturally occurring attacks. Among the individual API symptoms items at baseline (prelactate) only Afraid in general (r = 0.26) was significantly, but not strongly, correlated with the panic response. Controlling for baseline symptom levels, the most robust partial correlations of symptomatic increment with panic were Desire to flee (0.70), Fear of losing control (0.57), Afraid in general (0.49), and Dyspnea (0.48). Using a dichotomized symptom increment greater than 1, 13 of 29 API items indicated a panic response to lactate infusion; the best were Dyspnea, Feeling confused, Afraid in general, Difficulty speaking, Difficulty concentrating, Desire to flee, and Fear of losing control. A logistic regression analysis showed that among baseline measures, Afraid in general and Feeling confused significantly predicted panic. For dichotomized change scores, Afraid in general, Dyspnea, and Dizziness/lightheadedness significantly indicated panic. In these analyses three symptom items stand out as the most predictive and revealing of panic to lactate infusion: Afraid in general, Dyspnea, and Desire to flee. These results are discussed in the context of Klein's (1993) suffocation false alarm theory of panic.

Dose-Response Relationship, Drug↗
PubMed2003

Impact of alphacypermethrin treated bed nets on malaria in villages of Malkangiri district, Orissa, India.

The impact of use of bed-nets treated with alphacypermethrin, at 20 mg (ai)/m2, in comparison to untreated nets or no nets on malaria vectors and malaria incidence was studied in tribal villages of Malkangiri district, Orissa state, India, which are highly endemic for falciparum malaria. Treated or untreated nets were supplied to the villagers in June 1999 and the nets were re-treated in September 1999, just before the rise in vector abundance and malaria incidence. The seasonal pattern of indoor resting Anopheles fluviatilis females was similar in all the three groups of villages before the start of intervention and the indoor resting catches were not significantly different between treatment-groups (two-way ANOVA, F = 1.53; d.f. = (2, 78); P = 0.2). During intervention, the indoor resting catches differed significantly among treatment groups (two-way ANOVA, F = 38.9; d.f.= (2, 66); P < 0.005). There was a 99% reduction in the indoor resting catches of An. fluviatilis in villages with treated nets and 61% reduction in villages with untreated nets compared with no-net villages. Comparison between villages with and without treated nets showed that there was 97% reduction in indoor resting catches in villages with treated nets. Pair-wise comparison showed that the reductions between villages with and without nets as well as between villages with treated and untreated nets were significant (Dunnett's C-test, P < 0.05). The indoor resting catches of Anopheles culicifacies did not differ significantly among the three groups of villages either before (F = 0.99; d.f. = (2, 121); P = 0.4) or during intervention (F = 0.21; d.f. = (2, 66); P = 0.8). Bioassay with 3 min exposure to treated bed nets showed 100% mortality of An. culicifacies for 2 months and with An. fluviatilis for 4.5 months after which tests were not carried out. In villages with treated nets, the Annual Parasite Incidence (API) significantly declined (P < 0.05) by about 65.7% and prevalence of infection among children (< 15 years) declined by 57.1%, whereas in villages with untreated nets, there was only 34% reduction in API and 13% in the prevalence of infection. In villages with treated nets, there was 48% reduction in API and 64% in prevalence of infection compared with villages with untreated nets. The impact of use of treated bed nets on other arthropod pests lasted for at least 1.5 months. After 1.5 months, observations on arthropod pests were not continued. The use rate of treated nets varied from 49.8 to 93.7% in three seasons and about 68.3% of treated bed nets and 60% of untreated nets were in good condition 1 year after distribution. Out of 489 users of treated net, five people complained of a burning sensation on the face (skin irritation) for 5 days following the distribution of treated nets. There were no other complaints of any discomfort in using the treated nets. The use of alphacypermethrin treated bed nets at 20 mg (ai)/m2 can be one of the options for reducing the vector abundance and incidence of malaria in this area.

Animals↗
PubMed2006

Modeling the impact of direct phototransformation on predicted environmental concentrations (PECs) of propranolol hydrochloride in UK and US rivers.

There is currently uncertainty on the persistence of active pharmaceutical ingredients (APIs) and on their depletion mechanisms in natural surface waters such as rivers, and hence predictions of their fate are often poor. In this study, a beta-adrenergic receptor, propranolol hydrochloride, was selected as a model API to explore the relative significance of direct phototransformation as a potential removal process of hydrophilic APIs in rivers. Phototransformation kinetics of propranolol was measured under simulated solar irradiation in the laboratory, which were then converted to the kinetics applicable in UK and US rivers. The effects of light intensity, light penetration, river size and flow were examined. The extrapolated phototransformation half-lives were applied in the river catchment models of GREAT-ER and PhATE. Results demonstrated that direct phototransformation significantly reduced the predicted environmental concentrations of propranolol in the water phase. Predicted reductions of mean concentrations in the River Aire (UK) were 27% in summer and 3% in winter; and for the US rivers simulated, reductions were 28-68% in summer and 11-41% in winter. The highest reductions were predicted for long rivers with low turbidity and low flow conditions.

Biodegradation, Environmental↗
PubMed2005

Evaluation of ethoxynonafluorobutane as a safe and environmentally friendly solvent for chiral normal-phase LC-atmospheric pressure chemical ionization/electrospray ionization-mass spectrometry.

Coupling normal-phase LC separation methods to atmospheric pressure ionization (API)-mass spectrometry (MS) for detection can be problematic because of the possible detonation hazard and because nonpolar solvents do not support ionization of the analyte. Unlike achiral separations, enantiomeric separations can be very sensitive to small changes in the separation environment. Thus, completely substituting the main mobile phase component of a normal-phase LC solvent for an environmentally friendly, nonflammable fluorocarbon-ether as a safe and effective solvent must be thoroughly evaluated before it can be recommended for enantioselective separations with API-MS detection. Ethoxynonafluorobutane (ENFB) was used as a normal-phase solvent for the enantioselective separation of 15 compounds on two macrocyclic glycopeptide chiral stationary phases (CSPs) and a new polymeric chiral stationary phase. The chromatographic figures of merit were compared between results obtained with the ENFB mobile phases and traditional heptane-based mobile phases. In addition, the limits of detection (LOD) using the API-MS compatible ENFB were examined, as well as flow rate sensitivities and compatibilities with common polar organic modifier. ENFB is a safe and effective solvent for enantioselective normal-phase/API-MS analyses.

Atmospheric Pressure↗
PubMed2006

A new expert systems (SeDeM diagram) for control batch powder formulation and preformulation drug products.

The new SeDeM Method is proposed for testing the batch-to-batch reproducibility of the same active pharmaceutical ingredient (API) in powder form. The procedure describes the study of the galenic properties of substances in powder form in terms of the applicability of direct compression technology. Through experimental determination of the SeDeM Method parameters, and their subsequent mathematical treatment and graphical expression (SeDeM Diagram), three batches of the same API were analysed to determine whether it was suitable for direct compression. Batch-to-batch reproducibility of the results was verified. It was concluded that the SeDeM Method is suitable for testing batch-to-batch reproducibility of characteristics in powdered APIs substances. The results obtained confirm that the SeDeM Method is a useful, effective tool for drug-preformulation studies providing the pharmacotechnical data required when formulating a drug in tablet form. In addition, the results were effective for defining the most appropriate manufacturing technology.

Chemistry, Pharmaceutical↗
PubMed2005

Laser diffraction and image analysis as a supportive analytical tool in the pharmaceutical development of immediate release direct compression formulations.

Immediate release direct compression tablet formulations require a strict control of the particle characteristics (i.e. particle size (distribution) and shape) of both the active pharmaceutical ingredient (API) and the excipients. In this publication, the development of a dry dispersion laser diffraction (LD) method has been outlined. With this method, the chemical development of an API meant for the manufacturing of an immediate release direct compression tablet formulation can be supported. Comparison with static image analysis (SIA) and scanning electron microscopy (SEM) data often shows laser diffraction to generate different size data. However, since LD is fast and frequently shows an adequate precision over a wide particle size range, the technique is still considered as a valuable analytical tool in the screening of the particle size distribution of API batches. In the future, automated (static) image analysis and dynamic image analysis are believed to become more and more important, since these techniques will allow the fast analysis of large amounts of particles with a minimum intervention of the operator.

Chemistry, Pharmaceutical↗
PubMed2005

LC-UV method development and validation for the investigational anticancer agent imexon and identification of its degradation products.

Imexon (4-imino-1,3-diazabicyclo[3,1,0]-hexan-2-one) is a member of the class of 2-cyanoaziridine derivatives, which have been of interest as immunomodulators and anticancer agents since the late 1970s. The pharmaceutical development of imexon necessitated the availability of an assay for the quantification and purity determination of imexon active pharmaceutical ingredient (API) and the drug in its pharmaceutical dosage form. A liquid chromatographic (LC) method with ultraviolet (UV) detection was developed, using a reverse phase column with phosphate buffer (pH 6; 50 mM) as mobile phase and UV detection at 230 nm. Although retention capacity for imexon was small (capacity factor of 0.5), the method was found to be linear over the concentration range of interest of 1.0-25 microg/mL, precise, accurate, and stability-indicating. Moreover, the use of LC-mass spectrometry (MS) and on-line photodiode array (PDA) detection enabled us to propose structures for four degradation products. Two of these products were also found as impurities in the API. The degradation products, including chloro- and hydroxy-derivatised products were shown to arise from nucleophilic reactions with the activated aziridine moiety of imexon. The developed LC-UV method was found suitable for the pharmaceutical quality control of imexon API and the drug in its pharmaceutical dosage form.

Antineoplastic Agents↗
PubMed2005

Development and validation of an LC-UV method for the quantification and purity determination of the novel anticancer agent C1311 and its pharmaceutical dosage form.

C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. The pharmaceutical development of C1311 necessitated the availability of an assay for the quantification and purity determination of C1311 active pharmaceutical ingredient (API) and its pharmaceutical dosage form. A reversed-phase liquid chromatographic method (RP-LC) with ultraviolet (UV) detection was developed, consisting of separation on a C18 column with phosphate buffer (60 mM; pH 3 with 1 M citric acid)-acetonitrile-triethylamine (83:17:0.05, v/v/v) as the mobile phase and UV-detection at 280 nm. The method was found to be linear over a concentration range of 2.50-100 microg/mL, precise and accurate. Accelerated stress testing showed degradation products, which were well separated from the parent compound, confirming its stability-indicating capacity. Moreover, the use of LC-MS and on-line photo diode array detection enabled us to propose structures for four degradation products. Two of these products were also found as impurities in the API and more abundantly in an impure lot of API.

Aminoacridines↗
PubMed2005

Quantitative determination of captopril and prednisolone in tablets by FT-Raman spectroscopy.

A procedure for the quantitative determination of captopril and prednisolone in commercial tablets based on partial least squares (PLS) and principal component regression (PCR) treatment of FT-Raman spectroscopic data is described. In the studied medicines active pharmaceutical ingredients (APIs) constitute 4.2-16.7% of the tablet mass. Results obtained from calibration models built using unnormalised spectra were compared with the values found when an internal standard was added to each sample and the spectra were normalised by its selected band intensity at maximum or integrated. To appraise the quality of the models the relative standard error of predictions (RSEPs) were calculated for calibration and testing data sets. For captopril determination these were 1.8-2.2% (2.1-2.3%) and 2.7-3.1% (2.7-3.6%), respectively for the different PLS (PCR) models. For prednisolone these errors amounted to 1.8-2.1% (2.6-3.5%) and 3.2-3.7% (3.7-5.9%), respectively. Three commercial preparations of captopril containing 12.5mg and one 25mg of API per tablet were quantified using developed models. Found captopril contents, calculated versus results of iodometric titration, was equal 99.2-101.2% (99.2-102.0%), for the different PLS (PCR) calibration models and the different preparations. Quantification of prednisolone tablets, declared content 5mg per tablet, on the basis of PLS (PCR) models gave API amount, calculated versus results of UV-vis method, in the 99.0-101.0% (98.0-102.0%) range.

Algorithms↗
PubMed2005

Development and validation of a sensitive GC-MS method for the determination of trace levels of an alkylating reagent in a beta-lactam active pharmaceutical ingredient.

A direct injection gas chromatographic method utilizing selected-ion monitoring (SIM) mode mass selective detection was developed and validated for the trace analysis of an impurity, carbonic acid chloromethyl tetrahydro-pyran-4-yl ester (CCMTHP), present in a beta-lactam active pharmaceutical ingredient (API). A variety of analytical techniques including LC-MS, GC-FID, GC-ECD and GC-MS were evaluated during the method development. GC-MS with SIM at m/z=49 demonstrated the best detection sensitivity. A 10 ppm (5 pg on column) limit of quantitation (LOQ) was attained and the linearity of the method was demonstrated in the range of 10-1000 ppm. Accurate and precise quantitation of the impurity in drug substance was achieved with external standardization. A 10:1 split injection was applied to limit the amount of non-volatile API loading onto the column. The effects of injection and detection parameters such as split ratio, liner type, injection temperature and number of mass ions monitored were studied. Full validation proved the accuracy, precision and specificity of the method, which was successfully employed to analyze many pilot lots of the API.

Alkylating Agents↗