Medicine burden experiences of people living with HIV and association with stigma.

The medicine burden of people living with HIV (PLWH) is unknown. Between 2018 and 2020, participants completed a survey comprising outcome measures for medicine burden (LMQ-3) and stigma experiences (SSCI-8). Participants were HIV+ adults (≥18 years), using antiretrovirals (ARV) with or without non-ARV medicines, recruited via two outpatient clinics in southeast England and online via HIV charities across the UK. Spearman's correlations between medicine burden levels and stigma scores were calculated. Participants were mostly males (72%, 101/141) of mean (SD) age 48.6 (±12.31) years. Total number of medicines ranged from 1-20. High medicine burden was self-reported by 21.3% (30) and was associated with polypharmacy (≥ 5 medicines) (101.52 Vs 85.08, p = 0.006); multiple doses versus once daily regimes (109.31 Vs 85.65, p = 0.001); unemployment (98.23 Vs 84.46, p = 0.004); and ethnicity (97 Vs 86.85, p = 0.041 for non-White versus White participants). A correlation between medicine burden and stigma was observed (r = 0.576, p < 0.001). The LMQ-3 demonstrated adequate construct validity and reliability (domain loadings ranging 0.617-0.933 and Cronbach's α of 0.714-0.932). Assessment of medicine burden and psychosocial stigma in PLWH could enable identification of those needing additional support in future research and practice.

Screening for atrial fibrillation in care homes using pulse palpation and the AliveCor Kardia Mobile® device: a comparative cross-sectional pilot study.

BACKGROUND: Atrial fibrillation (AF) is a major cause of stroke in older people. Exacerbated by age and co-morbidities, residents of care homes are more likely to develop AF and less likely to receive oral anticoagulants. AIM: To determine the prevalence of AF using the design and methodology of the Pharmacists Detecting Atrial Fibrillation (PDAF) study in a care home setting. METHOD: A cross-sectional AF screening pilot study within four UK care homes, three residential and one residential/nursing. Screening followed the original PDAF protocol: a manual pulse check, followed by a single-Lead ECG (SLECG, AliveCor Kardia Mobile (KMD)) delivered by a pharmacist. All recorded SLECG were reviewed by a cardiologist and any residents requiring follow-up investigations were referred to their general practitioner. RESULTS: Fifty-three of 112 care home residents participated. From 52 SLECGs recorded, the cardiologist interpreted 13.5% (7/52) as having possible AF of which 9.6% (5/52) were previously unknown. One resident with previously unknown AF received anticoagulation. CONCLUSION: This study has shown a need for AF screening in care homes and that elements of the PDAF screening protocol are transferable in this setting. Early diagnosis and treatment of AF are essential to reduce the risk of stroke in this population.

Circadian entrainment and its role in depression: a mechanistic review.

The natural rotation of the earth generates an environmental day-night cycle that repeats every 24 h. This daily transition from dawn to dusk provides one of the most important time cues to which the majority of organisms synchronise their activity. Under these conditions, natural light, a photic stimulus, provides the principal entraining cue. In mammals, an endogenous circadian pacemaker located within the suprachiasmatic nucleus (SCN) of the hypothalamus acts as a coordinating centre to align physiological activity with the environmental light-dark cycle. However, the SCN also receives regulatory input from a number of behavioural, non-photic, cues such as physical activity, social interactions and feeding routines. The unique ability of the SCN to integrate both photic and non-photic cues allows it to generate a rhythm that is tailored to the individual and entrained to the environment. Here, we review the key neurotransmitter systems involved in both photic and non-photic transmission to the SCN and their interactions that assist in generating an entrained output rhythm. We also consider the impact on health of a desynchronised circadian system with a focus on depressive affective disorders and current therapies aimed at manipulating the relationship between photic and non-photic SCN regulators.

Dose-response relationship and reproducibility of urinary salbutamol excretion during the first 30 min after an inhalation.

AIMS: To determine the reproducibility and dose-response relationship for urinary salbutamol excretion post inhalation. METHODS: Fifteen volunteers inhaled either one, two, three, four or five doses of 100 micro g salbutamol on separate days and then seven of these also repeated each of the one, three and five doses on five occasions. After each study dose urine was collected 30 min post inhalation. RESULTS: The mean (SD) 30 min urinary salbutamol after one, two, three, four and five doses was 2.61 (1.0.), 5.47 (1.59), 8.68 (2.73), 12.34 (3.96) and 15.99 (4.50) micro g, respectively. Statistical analysis revealed a linear relationship (P < 0.001). Mean (SD) coefficient of variation after one, three and five doses was 10.5 (3.6), 10.1 (2.7) and 9.4 (2.3)%. CONCLUSIONS: The 30 min salbutamol urinary excretion post inhalation pharmacokinetic method, to compare inhaled products, is linear with inhaled dose and reproducible.

Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization.

AIMS: Clinical studies comparing nebulized drug delivery systems could be flawed because of the high doses used. We have compared lung and total systemic delivery of salbutamol from a nebuliser with that from a metered dose inhaler by measuring urinary recovery of drug and its sulphate metabolite. METHODS: Twelve healthy volunteers provided urine samples at 0, 0.5, 1, 2, 4, 8, 12 and 24 h after the start of dosing. Formulations and doses were 5 x 100 microg oral solution (ORAL), 5 x 100 microg from a metered dose inhaler (MDI), 2.5 mg using a nebuliser (NEB) and NEB with 25 g oral charcoal (NEBC). Each study phase was separated by 7 days and the order of dosing was randomized. RESULTS: Mean (s.d.) 30 min urinary salbutamol excretion after ORAL, MDI, NEB and NEBC was 0.4 (0.7), 12.1 (3.7), 15.0 (3.9) and 18.2 (5.7) microg, respectively (all P<0.001 compared with ORAL). When normalized for the dose available for inhalation from MDI, NEB and NEBC, the mean (s.d.) 30 min urinary excretion of salbutamol was 2.4 (0.7), 2.9 (0.6) and 2.7 (0.6)%, respectively, with a mean ratio (90% confidence interval) between NEB and NEBC, of 95.3 (91.1, 99.5)%. The mean (s.d.) excretion of salbutamol plus its metabolite over 24 h post ORAL, MDI, NEB and NEBC dosing was 297.9 (38.3), 290.3 (41.4), 266.5 (44.6) and 151.7 (40.9) microg, respectively. The mean ratio (90% confidence interval) between MDI and ORAL, and NEB and ORAL were 97.5 (94.1, 101.0) and 90.7 (81.2, 100.2)%, respectively. The NEBC data indicate that 6.07 (1.04)% of the nominal nebulized dose was delivered to the lungs. CONCLUSIONS: The 30 min urinary recovery of salbutamol, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the lung deposition of nebulized systems. Similarly, the urinary 24 h recovery of salbutamol plus its metabolite, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the delivery of nebulized drug to the systemic circulation.

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser.

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.

Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged.

AIMS: Urinary salbutamol post-inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated. METHODS: On separate study days volunteers received salbutamol 5 x 100 microg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5x100 microg doses from the MDI on five separate occasions and provided urine 0-30 min post dose. RESULTS: No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) microg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0-30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 x 100 microg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3)%. CONCLUSIONS: The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.

Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion.

AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.

Validation of a high-performance liquid chromatography assay for urinary nedocromil sodium following oral and inhaled administration.

The validation of a solid-phase extraction and an ion pair high-performance liquid chromatographic assay for the determination of nedocromil sodium (NCS) in urine samples following oral and inhaled administration to healthy volunteers is described. NCS and its internal standard sodium cromoglycate (SCG) were extracted from urine samples using solid-phase extraction and then quantified using high-performance liquid chromatography (HPLC). A 25-cm C8 Spherisorb 5 microm stationary phase with a mobile phase containing a long alkyl chain ion-pair reagent (methanol-0.045 M phosphate buffer-0.05 M dodecyl triethyl ammonium phosphate; 550:447.6:2.4, v/v) was used. The mean (S.D.) intra-day accuracy and precision of the HPLC assay was 99.9 (1.6) and 7.05 (4.9)%, respectively. These values for the inter-day data were 102.4 (4.07) and 10.5 (2.7)%, respectively, over the concentration range investigated. The method described permits the detection of NCS in human urine at concentrations as low as 0.04 microg ml(-1) where the signal-to-noise ratio is greater than 3:1. In 10 healthy volunteers a significantly greater amount of NCS was excreted in the urine following inhalation than after oral dosing (p<0.001). The mean (S.D.) amount of NCS renally excreted at 0.5, 1.0 and 24 h following inhalation of four 2-mg doses of NCS from a metered dose inhaler (MDI) was 0.513 (0.24), 1.163 (0.49) and 4.00 (1.73)% of the nominal dose. Similar values after oral administration of 8 mg of NCS were 0.026 (0.03), 0.079 (0.06) and 0.930 (0.74)%, respectively.

Determination of the relative bioavailability of nedocromil sodium to the lung following inhalation using urinary excretion.

OBJECTIVE: To determine the relative lung deposition of nedocromil sodium following inhalation by comparing the amounts of nedocromil sodium excreted in the urine after oral and inhaled dosing. METHODS: Ten healthy volunteers swallowed 8 mg of nedocromil and inhaled 4 x 2-mg doses on separate days. Urine was collected at 0.0, 0.5. 1.0, 2.0, 5.0, 24 h and 36 h after dosing. Urinary excretion of nedocromil was determined by high-performance liquid chromatography. RESULTS: A significantly greater amount of nedocromil was excreted following inhalation than after oral dosing. The mean with (SD) amount excreted at 0.5, 1.0 h and 24 h following inhalation of 4 x 2-mg doses was 41.0 (19.5), 93.0 (39.1) and 319.9 (138.1) microg. Corresponding values after oral administration of 8 mg of nedocromil were 2.1 (2.2), 6.3 (4.7) microg and 74.4 (58.8) microg, respectively. CONCLUSION: Nedocromil excreted in the urine at 0.5 h and 1.0 h after dosing is representative of the amount of drug delivered to the lungs. This method could be used to compare the relative bioavailability to the lungs following inhalation, and hence the performance of different inhaled products and inhalation techniques. The amount of nedocromil excreted in 24 h post-dose is representative of the emitted dose which was delivered to the body.

Development and validation of an ion-pair liquid chromatographic method for the quantitation of sodium cromoglycate in urine following inhalation.

An ion-pair liquid high-performance chromatography method with solid-phase extraction for measuring urinary concentrations of sodium cromoglycate following inhalation has been developed and validated. Sodium cromoglycate was extracted from urine on a 100-mg phenyl cartridge (Isolute, Jones Chromatography) and then quantified on a 25-cm C8 Spherisorb 5 microns stationary phase with a mobile phase of methanol-0.045 M phosphate buffer-0.05 M dodecyl triethyl ammonium phosphate (550:447.6:2.4, v/v) pH 2.3, at 0.85 ml min-1 using nedocromil sodium as an internal standard and UV detection at 238 nm. The inter- and intra-day reproducibilities were 8.33 and 13.63%, respectively, at 0.25 mg l-1. The limit of determination for sodium cromoglycate was 0.25 mg l-1 (with a signal-to-noise ratio of greater than 10:1). Following oral and inhaled administration of 20 mg of sodium cromoglycate to eight healthy volunteers, the mean and S.D. of sodium cromoglycate excreted in the urine at 0.5, 1 and 24 h post-dose were 0.02, 0.05 and 0.33%, and 0.16, 0.30 and 1.55% of the dose, respectively. The urinary recovery of sodium cromoglycate at 0.5 and 1 h following inhalation can therefore be used to compare the amount of drug reaching the respiratory tract using different sodium cromoglycate inhaled products or inhalation methods.

High-performance liquid chromatographic determination of the enantiomers of cyclophosphamide in serum.

A high-performance liquid chromatographic (HPLC) achiral-chiral coupled assay to measure the serum concentration of the enantiomers of cyclophosphamide is described. The R- and S-enantiomers of cyclophosphamide were quantified using a 5-cm-long C1 Spherisorb 5-microns column, with switching of the eluent containing racemic cyclophosphamide onto a 10-cm-long alpha 1 acid glycoprotein column. The limit of determination was 1.25 mg l-1 for each enantiomer and the ratio of the enantiomers over the range 2.5 to 100 mg l-1 was I. Serum enantiomer concentrations in blood samples taken from patients receiving 0.30 to 0.75 gm-2 of intravenous racemic cyclophosphamide could be measured at least three half-lives post dose. In six patients no significant difference in the clearance of R- and S-cyclophosphamide was found.

Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma.

Ifosfamide is a chiral pro-drug which is administered clinically in its racemic form. Serum concentrations of rac-ifosfamide and its enantiomers were measured in 12 patients with lung carcinoma following a mean (+/- s.d.) intravenous dose of 4.2 (0.83) g infused over 1 h. The mean (+/- s.d.) volumes of distribution (VSS) of rac, (R)- and (S)-ifosfamide were 0.61 (0.17), 0.60 (0.16) and 0.61 (0.19) l kg-1, respectively. The mean (+/- s.d.) half-lives and clearances were 6.57 (1.69), 7.12 (1.92) and 5.98 (1.52) h and 0.065 (0.013), 0.060 (0.013) and 0.072 (0.014) l h-1 kg-1 for rac, (R)- and (S)-ifosfamide, respectively. The half-life of (S)-ifosfamide was significantly (P < 0.001) shorter than that of (R)-ifosfamide and it had a significantly higher clearance (P < 0.001). There was no significant difference in the volumes of distribution of the enantiomers. The clinical significance of the faster elimination of (S)-ifosfamide is not known.

Enantiomeric separation of R- and S-ifosfamide and their determination in serum from clinical subjects.

A method to measure racemic, R- and S-ifosfamide concentrations from the serum of patients receiving ifosfamide chemotherapy has been developed. The racemic ifosfamide concentrations are quantified on a separate system and then the ratio of the enantiomers is determined using an achiral-chiral coupled system. Racemic ifosfamide is separated on the achiral system using a C1 spherisorb stationary phase and the eluent containing analyte is selectively transferred to the chiral system for separation of the two enantiomers by an alpha 1 glycoprotein column. On both systems the mobile phase is 1% acetonitrite in 0.015 M phosphate buffer (pH 4) at a flow-rate of 1 ml/min. The retention times of S- and R-ifosfamide were 11.6 and 13.0 mins, respectively, with a resolution factor of 1.53. Serum concentrations at least three to four half-lives post-infusion were detected by this method. In ten patients, following a mean +/- S.D. 1-h infusion of 3.9 +/- 0.32 g racemic ifosfamide, the mean +/- S.D. clearances of R- and S-ifosfamide were 0.061 +/- 0.013 and 0.072 +/- 0.014 1 h-1 kg-1.

Ifosfamide enantiomers: pharmacokinetics in children.

Ifosfamide, like other oxazaphosphorine drugs, is chiral and there is some evidence, mainly from animal studies, of stereo-selective differences in metabolism, excretion and cytotoxic activity between the two enantiomers. The pharmacokinetics of racemic ifosfamide (RAC-IFO), R-ifosfamide (R-IFO) and S-ifosfamide (S-IFO) were studied in five children who received intravenous therapy with racemic ifosfamide on 3 consecutive days. The clearance of S-IFO was greater than that of R-IFO. The clearance value at the end of the infusion was faster than the respective rate measured at the beginning of or during the ifosfamide regimens in four children and, therefore, suggests autoinduction of elimination of both enantiomers.