Nicolau Syndrome (Embolia Cutis Medicamentosa): A Rare and Poorly Recognized Iatrogenic Cause of Cutaneous Thrombotic Vasculopathy.

Nicolau syndrome is a rare form of iatrogenic cutaneous necrosis which affects injection sites. Although classically associated with intramuscular injections, it may develop after subcutaneous or other routes of parenteral drug administration. Clinically, it manifests as necrotic ulcers that often develop in a background of erythematous and livedoid reticular patches. The histopathologic characteristics of Nicolau syndrome are poorly documented in the dermatopathology literature and features only rarely as one of the obscure causes of cutaneous thrombotic vasculopathy. We report a case of Nicolau syndrome developing secondary to subcutaneous injection of cyclizine to familiarize the clinicians and pathologists to this unusual condition. Given that it is potentially avoidable, pathologists should alert the clinicians to the possibility of Nicolau syndrome when a skin biopsy from an injection site shows signs of extensive thrombotic vasculopathy.

Bioequivalence study of cyclizine hydrochloride 50 mg tablets in healthy volunteers: a randomized, open-label, single-dose study.

BACKGROUND: Cyclizine is used in the treatment and prevention of nausea and vomiting. We aimed to demonstrate bioequivalence between two formulations of cyclizine 50 mg tablets. METHODS/RESULTS: This single-dose, two-treatment, two-period, two-sequence, open-label, randomized crossover study was conducted on 32 healthy male volunteers. The average values for Cmax, Tmax, AUC0-t and AUC0-inf were 21.50 ng/ml, 3.85 h, 423.71 ng.h/ml and 489.26 ng.h/ml, for cyclizine 50 mg (test) versus 20.39 ng/ml, 4.34 h, 410.56 ng.h/ml and 473.86 ng.h/ml for Valoid 50 mg (reference). The 90% CI of the mean ratios of Cmax (geometric mean ratio: 101.81 ng/ml), and AUC0-t (101.81 ng.h/ml) were within the bioequivalence range of 80 to 125%. Both drugs were well tolerated. CONCLUSION: Cyclizine 50 mg is bioequivalent to the reference.

Post-operative cyclizine misuse.

Cyclizine is commonly prescribed as an anti-emetic post-operatively. We report a case of a 51-year-old woman who developed addiction to intravenous cyclizine following regular administration at recommended doses. This is the first report of cyclizine misuse post-operatively. We compare this case to cyclizine abuse reported amongst other populations. Prescribers should be aware of the potential of cyclizine as a drug of abuse.

The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients.

CONTEXT: Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype. OBJECTIVES: To deduce the pharmacokinetics and antiemetic/sedative effects of cyclizine and relate these and its metabolic ratio to the CYP2D6 genotype in palliative care patients. METHODS: Palliative care patients initiated on continuous cyclizine subcutaneous (SC) infusions had blood samples taken and efficacy/toxicity scores measured during the approach to steady state. Another group of patients at steady state receiving oral cyclizine had a single blood sample taken. Samples were analyzed to elucidate pharmacokinetic parameters and CYP2D6 genetics. RESULTS: SC dosing group: The median (interquartile range) cyclizine half-life, volume of distribution, and clearance were 13 (7-48) hours, 23 (12-30)L/kg, and 15 (11-26)mL/min/kg, respectively. Nausea and sedation scores were 3.0 (1.2-5.7) and 5.0 (2.6-8.1), respectively, overall and did not vary with genotype (P=0.76 and 0.11, respectively). The median overall metabolic ratio at steady state was 4.9 (3.8-9.2) and did vary with CYP2D6 genotype (P=0.02). Oral dosing group: The median metabolic ratio was 2.1 (1.5-2.9) and did not vary with CYP2D6 genotype (P=0.37). CONCLUSION: Palliative care patients have similar cyclizine pharmacokinetics to those reported in other patient groups. Cyclizine metabolism to norcyclizine may include CYP2D6 as the metabolic ratio varied with CYP2D6 genotype in the SC group.

Incidence and causes for syringe driver site reactions in palliative care: A prospective hospice-based study.

BACKGROUND: Syringe drivers are routinely used in palliative care for the subcutaneous infusion of drugs for pain and symptom control. Local site reactions occurring at the site of infusion can lead to patient discomfort and the potential for sub-optimal symptom control. AIM: The aim of this study was to investigate whether there was a correlation between drugs administered subcutaneously via a syringe driver and the incidence of syringe driver site reactions, further linking this to time to syringe driver site reaction. DESIGN: Prospective quantitative data collection of syringe driver use for 170 hospice inpatients. SETTING/PARTICIPANTS: Specialist palliative care inpatient facility in the UK. Syringe driver recording forms were retrieved from case notes of consecutive patients who received medication via a syringe driver. RESULTS: An association between the presence of cyclizine and levomepromazine and the incidence of syringe driver site reactions was identified. A marked difference in incidence of syringe driver site reaction was observed between the two study centres (26.5% vs. 7.7%). Although baseline patient characteristics were comparable, a difference in practice between the centres was identified, i.e. use of parenteral cannulae. An association between the time a syringe driver was in situ and the occurrence of a syringe driver site reaction was also demonstrated. CONCLUSIONS: Recommendations can be made for the frequency of syringe driver site changes based on which drugs are in use. Incidental findings from the study have been used to change practice at the hospice study site, with regard to choice of parenteral cannulae.

Acute eosinophilic pneumonia caused by calcium stearate, an additive agent for an oral antihistaminic medication.

A 70-year-old man was admitted to our hospital because of dyspnea after taking an antihistaminic agent (homochlorcyclizine hydrochloride) for itching. Chest roentgenogram showed infiltration in the left lung field, and laboratory data revealed eosinophilia. Examination of the bronchoalveolar lavage fluid revealed an increased eosinophil count. A drug lymphocyte stimulation test was positive only for calcium stearate, an additive contained in the homochlorcyclizine hydrochloride tablet. The pulmonary infiltration and clinical symptoms subsided after withdrawal of all drugs and initiation of glucocorticoid therapy. Therefore, we concluded that this patient's pulmonary disease was caused by calcium stearate, an additive for an antihistaminic drug. An allergic reaction to a drug's additive material should be considered as a rare cause of drug-induced acute eosinophilic pneumonia.

Percutaneous absorption of cyclizine and its alkyl analogues.

Cyclizine (I) alkyl analogues (II-IV) were synthesized and their skin permeation parameters evaluated in vitro. It was hoped that these compounds would possess physicochemical properties more favourable for percutaneous delivery than (I). The identification and levels of purity for the compounds were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry, and infrared spectrometry (IR) while melting points were determined by an electrothermal digital Bupsilonchi melting point apparatus. Aqueous solubilities (25 degrees C) and partition coefficients were determined and in vitro permeation studies were performed in buffer (37 degrees C) at pH 7.4 over a period of 24 h, using Franz diffusion cells fitted with human epidermal membranes. Generally, the analogues were more lipophilic, but nevertheless possessed higher aqueous solubilities as compared to (I). (II) and (IV) exhibited two- to three-fold increase in aqueous solubility and their melting temperatures dropped by more than 55 degrees C. Compound (III) had similar aqueous solubility to (I), but its melting point dropped by about 35 degrees C. Measured steady-state fluxes indicated that (II) is a far better penetrant (J=6.95 microg/cm(2)/h) of human epidermis than (I). Although fluxes of (III) and (IV) drop off markedly from that of (II), they remained above the flux of (I), which is (0.132 microg/cm(2)/h). In conclusion, (II) was the best skin permeant and also exhibited the highest aqueous solubility and lowest level of crystallinity as compared to (I) and other analogues. (III) and (IV) were more lipophilic. The overall permeation data of this series indicated that the more water-soluble and the lowest melting point compound was the best skin permeant.

Improving the acceptability of the atrial defibrillator for the treatment of persistent atrial fibrillation: the atrial defibrillator sedation assessment study (ADSAS).

BACKGROUND: To compare the acceptability and effectiveness of three pre-medication regimens for manually activated cardioversion of recurrent persistent atrial fibrillation. METHODS: Eighteen patients implanted with the Jewel AF atrial defibrillator for drug-resistant persistent atrial fibrillation only were studied in an open-labelled randomised crossover study. Patients were assigned to sedation (S) with midazolam elixir, analgesia (A) with morphine sulphate or combination therapy (C) with dextromoramide and lorazepam. Pre-medication was taken up to 1 h before cardioversion. Patients rotated through each type of medication after undertaking at least one cardioversion. Visual analogue scales were completed immediately post-cardioversion and 24 h later for pain, anxiety and 'unpleasantness'. Higher scores represented a worse outcome. RESULTS: After 2 years' follow-up, 238 cardioversions were performed with S, 17 with A and 35 with C. The mean immediate combined score for S (10.9, 95% confidence interval (CI) 8.2-13.6) was significantly lower than for A (17.3, 95% CI 15.1-19.5, P = 0.01) and for C (15.9, 95% CI 12.3-19.6, P = 0.02). All patients who used S chose it as the most favourable pre-medicant. All patients who used A found it the least acceptable. CONCLUSION: Sedation rather than analgesia enhanced the acceptability of manually activated atrial defibrillation.

Patterns of ergotamine and sumatriptan use in the Netherlands from 1991 to 1997.

The objective of this study was to assess usage patterns of ergotamine and sumatriptan over a period of 6 years, primarily to evaluate the impact that sumatriptan has had on the prescription of ergotamine. This study used ergotamine and sumatriptan prescription data representing inhabitants of eight cities in the Netherlands and covering the period of 1991-1997. The yearly incidence of new users between 1991 and 1997 was estimated for both drugs as well as for the drug of first choice to be prescribed to patients initiating specific abortive migraine treatment with either ergotamine or sumatriptan. Intra-individual ergotamine and sumatriptan usage patterns, characterized by single (incidental), continuous (rate of retention) or switch use, were examined for five patient cohorts, each for a follow-up period of 1 year. During the year of sumatriptan introduction (1991-1992), the overall incidence of new use for both drugs was highest (5.4 per 1000 inhabitants). Hereafter, a substantial reduction of more than 50% was observed. From 1992 to 1996, the yearly incidence of ergotamine first-time use was significantly higher than that of sumatriptan and up to 1996 ergotamine was more than twice as likely than sumatriptan to be prescribed to patients initiating specific abortive treatment. Hereafter, sumatriptan was as likely as ergotamine to be prescribed as the drug of first choice, which coincided with the full reimbursement of sumatriptan tablets. Overall, neurologists were more likely than general practitioners (GPs), to prescribe sumatriptan as the drug of first choice. Approximately half of the total study population were identified as single-time users. This phenomonen occurred more frequently in the ergotamine cohorts. The sumatriptan cohorts displayed a slight yet significant stronger retention rate compared with the ergotamine cohorts. The overall impact of sumatriptan on ergotamine use in The Netherlands was marginal, predominantly due to GP's adherence to migraine treatment guidelines and reimbursement policies concerning sumatriptan tablets. Overall, incidental use was relatively high and may reflect the reported difficulties in diagnosing migraine, lack of patient-doctor consultation, or that anticipated benefits of the drug were not achieved. Further study is required to clarify these issues.

Drugs and syringe drivers: a survey of adult specialist palliative care practice in the United Kingdom and Eire.

Subcutaneous delivery of drugs using a syringe driver is common practice within specialist palliative care units. There is, however, little documented information regarding clinical practice. A survey performed in 1992 reported that at least 28 drugs were used in combination with others in a single syringe driver. The aim of the present study was to reassess practice in this field and to enquire more specifically about newer drugs. Postal questionnaires were sent to all adult specialist palliative care in-patient units in the UK and Eire (n = 208). One hundred and sixty-five units (79%) responded. The most common syringe driver in use was the Graseby 26 (61% of responding units). Most units delivered the contents of the syringe over 24 h, and water was usually used as the diluent in 90% of cases. The maximum number of drugs that respondents were prepared to mix in a single syringe was usually three (51%) or four (35%). In the UK, all units used diamorphine in doses from 2.5 mg/24 h upwards. All respondents also used haloperidol, in doses from 0.5 to 60 mg/24 h. A total of 28 different drugs were used in syringe drivers. The most common combinations were diamorphine and midazolam (37%), diamorphine and levomepromazine (35%), diamorphine and haloperidol (33%), and diamorphine and cyclizine (31%). In conclusion, there is much in common with regard to the way in which drugs are delivered in syringe drivers. However, a wide variety of drugs and drug combinations are still in use.

Impact of an antiemetic protocol on postoperative nausea and vomiting in children.

The objective of the study was to demonstrate a decreased incidence of postoperative nausea and vomiting (PONV) in children through the use of an antiemetic protocol. PONV was recorded in children (1.5-15 years) after inpatient surgery under general anaesthesia in a prospective, interview based survey. Group 1 consisted of children having surgery 1 month before the introduction of a formalized antiemetic protocol and group 2, 2 months after its introduction. Data were collected over a 1-month period in each group. Outcome measures of nausea, emesis, antiemetic requirement and patient satisfaction were monitored for the first 24-h postoperative period. There were 272 children enrolled: 138 in group 1 and 134 in group 2. There was a difference between the two groups for gender (P=0.03), type of surgery (P=0.017), perioperative opioid (P=0.003) and perioperative antiemetic use (P=0.024). However, multivariate analysis did not demonstrate an impact on outcome from these factors. The incidence of postoperative nausea (PON) and postoperative vomiting (POV) following the introduction of the protocol was 36% and 34%, respectively. Moderate to severe nausea was decreased after introduction of the protocol (18% versus 9%, P=0.028) but moderate to severe vomiting failed to reach significance (19% versus 11%, P=0.078). The proportion of children who had repeated nausea decreased after the introduction of the protocol (17% versus 8%, P=0.02) but repeated episodes of vomiting remained unchanged (19% versus 14%). This was attributed to a significant increase in antiemetic prescribing by protocol in group 2 (10% versus 59%, P < 0.001). Patient satisfaction was high in both groups (85% versus 90%). The introduction of a postoperative antiemetic protocol improved prescribing frequency. This resulted in a decreased incidence of moderate to severe PON and a reduction in the number of patients with repeated nausea.

Drug combinations in syringe drivers: the compatibility and stability of diamorphine with cyclizine and haloperidol.

The compatibility and stability of 2B combinations of diamorphine hydrochloride (5-100 mg/ml) with cyclizine lactate (5-50 mg/ml), eight combinations of diamorphine (10-100 mg/ml) with haloperidol (2-4 mg/ml) and eight combinations of all three drugs was assessed after storage in 1 ml polypropylene syringes. Samples were stored for periods up to seven days in the light and at room temperature (22 degrees C). Five combinations of diamorphine with cyclizine precipitated immediately upon preparation. After analysis and determination of t90% values (the time taken for 10% degradation). 16 of the remaining 23 combinations were judged to be compatible (no signs of crystallization or precipitation) and stable (less than 10% loss of potency of either drug) after storage for 24 h. After seven days storage only four remained compatible and stable. The results indicate that ratios of diamorphine to cyclizine of 1:1 are stable at concentrations up to 20 mg/ml. An increase in diamorphine concentration necessitates a reduction in cyclizine to 10 mg/ml, and an increase in cyclizine concentration necessitates a reduction in concentration of diamorphine to 15 mg/ml to maintain stability over 24 h. All the combinations of diamorphine with haloperidol remained compatible and stable for seven days. The addition of haloperidol (2 mg/ml) to the diamorphine and cyclizine combinations had no detrimental effect on their compatibility and stability. A stability curve is included as an easy way for palliative care personnel to avoid potential problems with incompatibilities and reduced stability when using these combinations. Furthermore, to reduce the possibility of precipitation with mixtures containing cyclizine, the use of 0.9% sodium chloride should be avoided.

A randomized double-blinded comparison of metoclopramide, ondansetron and cyclizine in day-case laparoscopy.

This study determined the overall incidence of postoperative nausea and vomiting (PONV) in 38 patients undergoing laparoscopic gynaecological procedures who received a standardized propofol/isoflurane anaesthetic but no preoperative antiemetic. A further 166 patients similarly anaesthetized were then randomly allocated to receive either metoclopramide 10 mg. ondansetron 4 mg, or cyclizine 50 mg as an intravenous antiemetic immediately preinduction. Overall incidence of PONV was determined for all groups and the relative efficacy of the three antiemetic agents assessed. Fifty per cent of patients in the initial group (no antiemetic) reported significant nausea and/or vomiting up to 24 hours postoperatively. The incidence of PONV in the metoclopramide group was 24%, in the ondansetron group 20%, and in the cyclizine group 51%. There was no detectable difference in relative efficacy between ondansetron 4 mg and metoclopramide 10 mg. The incidence of PONV in the group who received cyclizine was similar to that found in the pilot group who received no PONV prophylaxis. Both metoclopramide and ondansetron may potentially decrease the incidence of PONV following gynaecologic laparoscopy by up to 50% when administered intravenously prior to a propofol/isoflurane anaesthetic.

Local anaesthetic on Filshie clips for pain relief after tubal sterilisation: a randomised double-blind controlled trial.

Pain during tubal sterilisation is thought to be due to either ischaemia or pressure at the site of impact of sterilising devices on the fallopian tubes. We have evaluated the effectiveness of an application of 2% lignocaine gel to Filshie clips to relieve postoperative pain. In a randomised double-blind placebo-controlled study, 80 healthy women undergoing tubal sterilisation under general anaesthesia at the County Hospital, Lincoln, UK, were allocated to be sterilised by Flishie clips covered with 2% lignocaine gel or K-Y gel as placebo. Pelvic pain was assessed, with a 100 mm visual analogue scale, at 1 hour, at hospital discharge, and time of first analgesia or any other time analgesia was demanded. The lignocaine-treated group had significantly longer time to first analgesia, less pain at 1 hour, less nausea and vomiting, and shorter recovery time. Fewer lignocaine-treated patients needed additional analgesia and they required fewer opioids. There was no case of failed sterilisation or adverse reaction to lignocaine. The application of local anaesthetic gel to Filshie clips is a safe, non-invasive, and effective method of relieving postoperative pain during laparoscopic tubal sterilisation.

Enantioselective pharmacokinetics of homochlorcyclizine: disposition of (+)- and (-)-homochlorcyclizine after intravenous and oral administration of racemic homochlorcyclizine to rats.

Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg-1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg-1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (-)-isomer. The AUC0-infinity values of the (+)- and (-)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (-)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.

Gas gangrene following intra-arterial injection of oral medication in a drug abuser.

We report a patient in whom intra-arterial injection of oral medication led to the development of fulminating gas gangrene and death, despite the initial clinical symptoms being minor. We believe that prophylactic antibiotics should be administered to patients following intra-arterial injection of oral medication especially if immunocompetence, such as from human immunodeficiency virus (HIV) infection, is likely.