High-throughput quantification of drugs and their metabolites in biosamples by LC-MS/MS and CE-MS/MS: possibilities and limitations.

Off-line solid phase extraction with C18 disk plates and turbulent flow chromatography were evaluated versus on-line solid phase extraction using column-switching HPLC as sample preparation techniques for high-throughput analysis of pharmaceutical compounds and their metabolites by LC-MS/MS. Turbulent flow chromatography was found to be very straightforward in its applicaton, but the LOQs were more than fivefold higher compared with off-line or other on-line solid phase extraction methods. Solid phase extraction (SPE) on disk was found to be fast and sufficient efficient to minimize matrix effects and therefore an apprach to provide sensitive and reliable LC-MS/MS methods. Column-switching HPLC with microbore columns (0.5 mm i.d.) were used for fast analysis of a parent drug and four of its metabolites utilizing steep gradients in 1 minute. The application of CZE-MS/MS for bionalysis of pharamaceutical compounds is also discussed.

MSG.

The Microgravity Science Glovebox (MSG) has been designed as a modular multi-user facility for performing a wide variety of materials, combustion, fluids and biotechnology investigations in the microgravity environment. Primarily it provides an enclosed and sealed Work Volume (WV) equipped with lighting, mechanical, electrical, data, gas and vacuum connections, and thermal control. The WV is provided with built-in glove ports for safe handling by the crew and isolates the item under investigation from the operator area and the general ISS environment. An attached Airlock (AL) allows specimens and tools to be inserted or removed during MSG operations with limited environmental exchange between the WV and the ISS cabin. The MSG facility will also accommodate minor repair/servicing of hardware requiring a clean and/or an encapsulated working environment (e.g. the Fluid Science Laboratory's investigation containers).

Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.

AIMS: This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888. METHODS: The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebo-controlled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban. RESULTS: At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance. CONCLUSIONS: With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.

Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies.

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.

Simultaneous determination of a potassium channel opener and its metabolite in rat plasma with column-switching liquid chromatography using atmospheric pressure chemical ionisation.

A specific LC-MS assay was developed for simultaneous determination of Ro 31-7837 (I) and its metabolite Ro 31-6930 (II) in rat plasma, using on-line SPE by column-switching reversed-phase HPLC combined with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry for detection in the selected reaction monitoring mode. The method involved precipitation of plasma proteins with ethanol and automatic injection of a 1-ml aliquot of the supernatant onto a standard bore trapping column (LC-ABZ, 20x4.6 mm) for compound retention. Using the backflush mode, the analytes were transferred onto the analytical column (Kromasil C18, 125x4.0 mm) for chromatographic separation and mass spectrometric detection. The mean precision and accuracy for I and II in the concentration range 0.25-100 ng/ml were found to be 3.7% and 101%, and 3.5% and 106%, respectively. The data were assessed from QC samples during the validation phase of the assay. The lower limit of quantification for both I and II was 0.25 ng/ml, using a 0.5-ml plasma aliquot. This LC-MS method provided the requisite specificity, sensitivity, accuracy and precision to assess the pharmacokinetics of the compounds in the rat.

Low picogram determination of Ro 48-6791 and its major metabolite, Ro 48-6792, in plasma with column-switching microbore high-performance liquid chromatography coupled to ion spray tandem mass spectrometry.

A coupled liquid chromatography/tandem mass spectrometry assay was developed for simultaneous determination of Ro 48-6791 and its secondary amine metabolite in human plasma samples with a quantification limit for both compounds of 1 pg/mL using a 1 mL plasma aliquot. The method exploits the enhanced mass sensitivity of a microbore (300 microns i.d.) reversed-phase capillary column coupled to an ion spray probe combined with tandem mass spectrometry. A straightforward column-switching system was utilized to focus the analytes onto a microbore trapping column following solid-phase extraction of a 50 microL plasma sample extract from liquid/liquid extraction. Backflushing of the retained analytes from the trapping column onto the microbore capillary column provided the requisite high peak concentration for high sensitivity. The inter-assay precision and accuracy for Ro 48-6791 and its metabolite, at 10 pg/mL, were found to be 3.4%, and 105%, and 9.1%, and 99.9%, respectively. The calibration curves were linear over the range 1 to 1000 pg/mL. The method proved to be sufficiently rugged for analysis of samples.

Column-switching high-performance liquid chromatography combined with ionspray tandem mass spectrometry for the simultaneous determination of the platelet inhibitor Ro 44-3888 and its pro-drug and precursor metabolite in plasma.

A liquid chromatographic/mass spectrometric (LC/MS) assay was developed for the simultaneous determination of a pro-drug (Ro 48-3657), its active metabolite (platelet inhibitor, Ro 44-3888) and precursor metabolite (Ro 48-3656) in human, dog and rat plasma, utilizing on-line column-switching solid-phase extraction (SPE) for clean-up and high-performance liquid chromatography (HPLC) for separation of the analytes, with on-line detection by ionspray (pneumatically assisted electrospray) tandem mass spectrometry in the selected reaction monitoring (SRM) mode. The assay was validated for the quantification of all three analytes. The method involves protein precipitation with perchloric acid, enrichment of the analytes on a standard bore trapping column (i.d. 4.6 mm) and separation on a narrow-bore analytical column (i.d. 2 mm). Except for the plasma precipitation step, the assay was fully automated, allowing unattended operation. The lower limits of quantification were 0.20 ng ml-1 (Ro 48-3657, Ro 44-3888) and 0.50 ng ml-1 (Ro 48-3656) using a 0.5 ml plasma aliquot. The mean inter-assay precision and accuracy derived from quality control samples were 5.3% and 101%, respectively, utilizing the calibration range 0.2-200 ng ml-1. Using the unique features of column-switching HPLC combined with MS/MS, it was possible to develop the method in a short period of time. The method has been successfully applied to map complete concentration-time courses for the kinetic evaluation of the drug and its metabolites in man, dog and rat. This LC/MS assay is sensitive, specific, accurate, precise and robust.

Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-6791, compared with midazolam, in healthy subjects during first administration to man studies. METHODS: The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first group, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg(-1). The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min(-1)) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. RESULTS: Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V(SS)) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 48-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. CONCLUSIONS: This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. METHODS: The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. RESULTS: Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. CONCLUSIONS: These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Pharmacokinetic-pharmacodynamic modelling of the EEG effects of Ro 48-6791, a new short-acting benzodiazepine, in young and elderly subjects.

The objectives of this study were to explore, by a modelling approach, in nine young (24-28 yr) and nine elderly (67-81 yr) male subjects, the pharmacokinetics and pharmacodynamics of Ro 48-6791, a new water soluble benzodiazepine. A microprocessor-controlled i.v. infusion pump generated linearly increasing arterial plasma concentrations until predetermined EEG and clinical end-points were attained. This concentration was maintained for 15 min and thereafter the infusion was discontinued. Haemodynamic and respiratory variables were monitored continuously. At full reorientation of the subject, a second infusion cycle was started under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time profiles of Ro 48-6791 were fitted accurately to an open three-compartment model. Plasma concentrations of Ro 48-6792, an N-dealkylated metabolite, accumulated during the course of the study. Pharmacokinetic variables of Ro 48-6791 were similar for both groups. The largest differences between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h-1) and k12 (11 (7) vs 7 (3) h-1). The concentration-median EEG frequency relationship was described with a sigmoid Emax model. Elderly subjects showed slightly increased drug sensitivity compared with young subjects (EC50 72 (25) and 44 (15) micrograms litre-1 in young and elderly subjects, respectively). The concentration-response data of the second infusion cycle deviated from the fitted curve suggesting either development of acute tolerance to the EEG effects of Ro 48-6791 or a role for drug metabolites. Because of the differences in sensitivity and clearance, lower doses of Ro 48-6791 should be administered to elderly compared with young subjects in order to achieve similar effects.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Elevator talk: observational study of inappropriate comments in a public space.

OBJECTIVES: We conducted a study to determine the type and frequency of inappropriate comments made by hospital employees while riding hospital elevators. METHODS: Four observers rode in elevators at five hospitals, listening for any comments made by hospital employees that might be deemed inappropriate. All potentially inappropriate comments were reviewed by the research team and were classified as inappropriate if they met at least one of the following criteria: violated patient confidentiality, raised concerns about the speaker's ability or desire to provide high-quality patient care, raised concerns about poor quality of care in the hospital (by persons other than the speaker), or contained derogatory remarks about patients or their families. RESULTS: We observed 259 one-way elevator trips offering opportunity for conversation. We overheard a total of 39 inappropriate comments, which took place on 36 rides (13.9% of the trips). The most frequent comments (18) were violations of patients confidentiality. Next most frequent (10 comments) were unprofessional remarks in which clinicians talked about themselves in ways that raised questions about their ability or desire to provide high-quality patient care. Other comments included derogatory statements about the general quality of hospital care (8) and derogatory remarks about patients (5). Physicians were involved in 15 of the comments, nurses in 10, and other hospital employees in the remainder. CONCLUSION: Inappropriate comments took place with disturbing frequency in the elevator rides we sampled. These comments did not exclusively involve violations of patient confidentiality, but encompassed a range of discussions that health care employees must be careful to avoid.

Flumazenil kinetics in the elderly.

In an open design, randomised, two-way cross-over study, a single 2 mg i.v. dose and a single 30 mg oral dose of flumazenil were each administered to a group of healthy young (n = 6) and elderly (n = 12) volunteers (male: female 2/1). Plasma samples were collected at intervals and intact drug was assayed. Both the i.v. and oral doses of flumazenil were very well tolerated by both age groups and no severe or unexpected adverse effects were observed. The main complaints were dizziness and headache, mainly after oral dosing, probably due to the higher Cmax and AUC following this route of administration. After 2 mg i.v. the disposition parameters in the two age groups (elderly/young) were very similar: volume of distribution (Vss): 0.88/0.90 l.kg-1; total body clearance (ClPL): 0.86/0.99 l.min-1; terminal elimination half-life (t1/2 beta): 1.02/0.91 h. After the 30 mg oral dose the mean Cmax of 87.6 ng.ml-1 (elderly) and 78.4 ng.ml-1 (young) were generally reached within 0.5 to 1 h. In 26% (elderly) and 23% (young), the absolute bioavailability of flumazenil was very similar. It is concluded that the absorption and disposition parameters of flumazenil were not significantly affected by aging.

Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative.

A highly sensitive capillary gas chromatographic method was developed to determine plasma levels of a novel partial benzodiazepine receptor agonist in man following the very low therapeutic doses required for anxiolysis. The compound was isolated from plasma by liquid-liquid extraction at basic pH, converted into the ethyl ester analogue by a two-step procedure, separated from plasma constituents by capillary gas chromatography and quantified by means of nitrogen-selective detection. Because of the thermolabile tert.-butyl ester function, the agonist could not be gas chromatographed without degradation. Formation of the far more stable ethyl ester analogue was achieved by treatment with hydrogen chloride in ethanol, followed by an ethylation step with diazoethane. The high sensitivity of the new method (about 100 pg/ml, using 1-ml plasma specimens) allowed the monitoring of plasma levels of the agonist for up to 8 h (about three elimination half-lives) after a single 0.1-mg oral dose to human volunteers. The practicability of the procedure was demonstrated by the analysis of more than 600 plasma samples from clinical studies performed with human volunteers.

Toxidrome recognition to improve efficiency of emergency urine drug screens.

We correlated clinical symptom complexes of drugs (toxidromes) to results of 204 consecutive toxicological screens ordered in our emergency department. The toxidromes were divided into eight categories: sedative hypnotic, narcotic, stimulant, coma-apnea-seizure, hallucinogenic, anticholinergic, unknown, and "no drugs." Emergency medicine nurses, clinical pharmacists, and medical residents were asked to choose one or more of the above toxidromes independently when ordering the toxicology screen. The nurses achieved the highest symptom complex recognition of the drug (55 of 61, 88%) followed by medical residents (76 of 90, 84%) and clinical pharmacists (27 of 34, 79.4%), but the differences were not statistically significant. We conclude that the major determinant in selecting correct toxidromes is clinical experience of the practitioners. Given the percentages of toxidrome recognition, it should be possible to increase efficiency of laboratory use by ordering tests only for the drugs clinically suspected in a particular toxic patient.

Serum lidocaine levels during arthroscopy using continuous irrigation with lidocaine.

Forty patients with symptoms of internal derangement of the knee were examined arthroscopically under local anesthesia using a continuous irrigation solution of 0.2% lidocaine. Serum levels were measured during and following the procedure to determine peak levels obtained and to assure that toxic levels were not exceeded. The procedure was well tolerated by all patients and found to be adequate by the surgeon. No procedure was terminated because of discomfort. Lidocaine levels ranged from undetectable to 2.5 micrograms/ml with an average of 0.6 microgram/ml. No complications of lidocaine toxicity were noted by the anesthesiologist or the operating surgeon. This technique provides a safe and efficient method of meeting the demands for diagnostic and therapeutic arthroscopy in ambulatory patients.

Experimental model for the investigation of kinetic and/or dynamic interactions between drugs and ethanol in humans.

This study was performed to establish an experimental method for the investigation of interactions between ethanol and drugs under predictable and controlled conditions. The model was tested with flumazenil (Ro 15-1788), a short-acting benzodiazepine antagonist with an elimination half-life of 1 h. Six healthy volunteers (5 males, 1 female) were administered ethanol by intravenous infusion with stepwise changing rates. The infusion rates were adapted to each subject on the basis of individual disposition parameters of ethanol, which were derived from preceding short-term infusions of 120 min duration (1.0 mg/kg in males, 0.8 mg/kg in the female). This two-step procedure led to individual ethanol plasma levels between 1.47 +/- 0.04 and 1.71 +/- 0.03 g/L, which were reached after 2.5 h and thereafter maintained over another 6 h. Within the period of constant ethanol levels, single doses of flumazenil and placebo, respectively, were injected intravenously as a bolus (2 min) in a double-blind fashion according to a randomized two-way crossover design. Three subjects received a dose of 0.10 mg/kg of flumazenil, and the remaining three subjects received a dose of 0.20 mg/kg. Evaluation of the plasma concentration time curves of flumazenil did not reveal evidence of an effect of ethanol on the pharmacokinetics of this drug.

Treatment of neuroleptic malignant syndrome with diphenhydramine.

A case report of a patient with neuroleptic malignant syndrome is described. Of note is the fact that both central and peripheral manifestations of the syndrome responded to diphenhydramine and suportive therapy alone. A brief review of therapy is also discussed.