Stability of anticholinergic load in Australian community-dwelling older people: a longitudinal analysis.

BACKGROUND: It is recommended that anticholinergic medication is avoided in older people, especially those with cognitive impairment. OBJECTIVE: To investigate anticholinergic load (ACL) over time in older primary care patients with and without cognitive impairment. METHODS: Community-dwelling general practice patients at baseline (n = 1768), at year one (n = 1373) and a restricted cohort (with possible or definite cognitive impairment) at year two (n = 370) had medication regimens documented by a research nurse during a home visit. Anticholinergic medicines were categorized as levels 1-3 (low-high potency) and summed for each participant as a measure of their ACL. RESULTS: Most participants had no change in ACL over time, but there was some turnover in the anticholinergic medications used. The mean change in ACL was 0.012 ± 0.99 from baseline to 12 months and -0.04 ± 1.3 from baseline to 24 months. Cardiovascular drugs were the most commonly used level 1 anticholinergics, followed by antidepressants and opioids. Antidepressants and urologicals were the most commonly used level 3 anticholinergics. The rate of anticholinergic deprescribing was equivalent to the rate of anticholinergic initiation, and commonly involved the level 1 drugs warfarin, furosemide and temazepam, and the level 3 drugs amitriptyline and oxybutynin. People with dementia had a higher ACL at baseline and year one compared with other participants. CONCLUSION: ACL of community-dwelling older people was very stable over time. This may represent lost opportunities for deprescribing as well as potentially inappropriate prescribing, particularly in those with cognitive impairment.

Involvement of Rho-kinase signaling pathways in nerve evoked and spontaneous contractions of the Guinea pig prostate.

PURPOSE: Men with benign prostatic hyperplasia commonly experience irritative lower urinary tract symptoms, which are due at least in part to enhanced prostatic smooth muscle tone. To provide some insight into the changes that occur in prostatic contractility with age, we examined the contribution of rho-kinase dependent Ca(2+) sensitization in neurogenic and spontaneous contractions of young and aging guinea pig prostates. MATERIALS AND METHODS: We used conventional tension recording and electrophysiological intracellular microelectrode recording techniques. RESULTS: The Rho-kinase inhibitor Y-27632 (10 and 100 µM) significantly inhibited electrical field stimulated evoked (neurogenic) contractions in the guinea pig prostate in a dose dependent manner. In addition, Y-27632 (1 and 10 µM) similarly suppressed tetrodotoxin insensitive spontaneous contractions in dose dependent fashion. While Y-27632 at 10 µM decreased spontaneous contractions of young and aging guinea pig prostates, as evidenced by a significant decrease in the AUC, there was no significant difference in the degree of inhibition between the 2 age groups. In contrast to contractile activity, Y-27632 did not affect the generation or modulation of spontaneous slow wave electrical activity, which underlies spontaneous contractions. CONCLUSIONS: There are strong indicators that Rho-kinase signaling pathways have a significant role in prostatic smooth muscle contractility, most likely independent of cytosolic Ca(2+) levels. Features of the rho-kinase pathway may well represent alternative, novel future therapeutic targets to reduce prostatic contractility, thereby alleviating the lower urinary tract symptoms arising from benign prostatic hyperplasia.

The effect of histamine on field-stimulated contractions of the guinea-pig prostate.

The aim of this study was to investigate the effect of histamine on field-stimulated contractions of the guinea-pig prostate using isolated preparations in organ bath experiments. The histamine receptor subtype involved in potentiating the twitch responses was characterised, and the presence of any post-synaptic effects was determined. In addition, the effects of histamine on nerve-stimulated contractions of the ventral and dorsal prostate as well as the coagulating gland were compared in preliminary experiments. Histamine (300 microM) approximately doubled the magnitude of the twitch contractions in the ventral and dorsal lobes of the prostate (nerve stimulation parameters were 10 Hz for 2 s every 50 s, 0.5 ms duration at supramaximal voltage). In the coagulating glands, histamine increased the contractions more than fourfold. Further experiments were performed only on the ventral glands. The H(1) receptor antagonist, mepyramine, exhibited an apparent competitive antagonism against the histamine-induced potentiations of the twitch responses (apparent pK(B) value = 9.21+/-0.17 (n=5). The H(2) receptor antagonist, ranitidine, produced a small, significant shift to the right, as did the time control. The H(3) receptor antagonist, thioperamide, had no significant effect on the concentration-response curve. The effects of histamine (10 microM) on exogenously applied acetylcholine (Ach), noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were determined. In each case, the contractile responses were significantly potentiated: ATP (5.8-fold P<0.0001, n=8), NA (1.6-fold P<0.05, n=10) and Ach (2.1-fold P<0.0007, n=10). This is the first study that has shown the effects of histamine on field-stimulated contractions in the prostate of any species. It is concluded that histamine, acting on H(1) receptors, elicits a considerable potentiation of the nerve-stimulated twitch contractions in the guinea-pig prostate. One mechanism whereby histamine exerts its potentiating effect is a post-synaptic enhancement of the response to ATP in particular, but also to NA and Ach. It is suggested that H(1)-receptor and purinoceptor antagonists may have a role to play in the treatment of benign prostatic hyperplasia (BPH).

Impact of multiple low-level anticholinergic medications on anticholinergic load of community-dwelling elderly with and without dementia.

BACKGROUND: Elderly people, particularly those with dementia, are sensitive to adverse anticholinergic drug effects. This study examines the prevalence of anticholinergic medication, and anticholinergic load and its predictors, in community-dwelling elderly patients (aged 75 years and older) in Australia. METHODS: A research nurse visited the home of each participant (n = 1,044), compiled a list of current medications, and assessed participants' cognitive status using a subsection of the revised Cambridge Examination for Mental Disorders of the Elderly (CAMCOG-R). Anticholinergic load was determined for each patient using the Anticholinergic Drug Scale (ADS). RESULTS: Multivariate analysis identified several patient factors that were associated with higher anticholinergic burden, including polypharmacy (i.e. taking five or more medications) (p < 0.001), increasing age (p = 0.018), CAMCOG-R dementia (p = 0.003), depression (p = 0.003), and lower physical quality of life (p < 0.001). The dementia group (n = 86) took a significantly higher number of medications (4.6 vs. 3.9; p = 0.04), and had a significantly higher anticholinergic load (1.5 vs. 0.8; p = 0.002) than those without dementia (n = 958). Approximately 60% of the dementia group and 40% of the non-dementia group were receiving at least one anticholinergic drug. This difference was due to the higher proportion of dementia patients taking level 1 (potentially anticholinergic) (p = 0.002) and level 3 (markedly anticholinergic) (p = 0.005) drugs. CONCLUSIONS: There is considerable scope for the improvement of prescribing practices in the elderly, and particularly those with dementia. Importantly, level 1 anticholinergics have been identified as major contributors to the anticholinergic load in people with dementia. Longitudinal studies are required to determine the effects of increased and decreased anticholinergic load on cognitive function and other clinical outcomes for people with dementia.

Phasic contractions of the mouse vagina and cervix at different phases of the estrus cycle and during late pregnancy.

BACKGROUND/AIMS: The pacemaker mechanisms activating phasic contractions of vaginal and cervical smooth muscle remain poorly understood. Here, we investigate properties of pacemaking in vaginal and cervical tissues by determining whether: 1) functional pacemaking is dependent on the phase of the estrus cycle or pregnancy; 2) pacemaking involves Ca2+ release from sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) -dependent intracellular Ca2+ stores; and 3) c-Kit and/or vimentin immunoreactive ICs have a role in pacemaking. METHODOLOGY/PRINCIPAL FINDINGS: Vaginal and cervical contractions were measured in vitro, as was the distribution of c-Kit and vimentin positive interstitial cells (ICs). Cervical smooth muscle was spontaneously active in estrus and metestrus but quiescent during proestrus and diestrus. Vaginal smooth muscle was normally quiescent but exhibited phasic contractions in the presence of oxytocin or the K+ channel blocker tetraethylammonium (TEA) chloride. Spontaneous contractions in the cervix and TEA-induced phasic contractions in the vagina persisted in the presence of cyclopiazonic acid (CPA), a blocker of the SERCA that refills intracellular SR Ca2+ stores, but were inhibited in low Ca2+ solution or in the presence of nifedipine, an inhibitor of L-type Ca2+channels. ICs were found in small numbers in the mouse cervix but not in the vagina. CONCLUSIONS/SIGNIFICANCE: Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips were normally quiescent but could be induced to exhibit phasic contractions independent on phase of the estrus cycle or late pregnancy. Spontaneous cervical or TEA-induced vaginal phasic contractions were not mediated by ICs or intracellular Ca2+ stores. Given that vaginal smooth muscle is normally quiescent then it is likely that increases in hormones such as oxytocin, as might occur through sexual stimulation, enhance the effectiveness of such pacemaking until phasic contractile activity emerges.

The guinea-pig oesophagus is a versatile in vitro preparation for pharmacological studies.

1. The isolated oesophagus of the guinea-pig is a useful preparation that can be used as an alternative to the phrenic nerve-diaphragm preparations that have been used traditionally in the determination of the actions of drugs and toxins at the neuromuscular junction. The guinea-pig isolated oesophagus can also provide information about effects at ganglionic nicotinic receptors, which are not present in the diaphragm preparations. 2. The muscularis externa of the body of the oesophagus consists exclusively of striated muscle fibres. The myenteric plexus is found between the outer longitudinally arranged layer and the inner circular layer. The muscularis mucosae contains smooth muscle fibres arranged longitudinally. 3. The vagal nerves are comprised of special vagal efferents that innervate the striated muscle fibres directly and 'parasympathetic' vagal fibres that synapse in the myenteric ganglia and, subsequently, affect the smooth muscle of the muscularis mucosae. Thus, both striated and smooth muscle responses to vagal nerve stimulation can be studied. In addition, afferent neurons run in the vagus. 4. Studies using various isolated oesophageal preparations have been reviewed. These consist of the whole oesophagus (including striated muscle, myenteric plexus and smooth muscle), the isolated mucosal layer (striated muscle and the myenteric plexus both absent) and the whole oesophagus with the vagus nerve attached. Comparative studies of the effects of drugs acting directly on the muscularis mucosae and/or indirectly via the intramural plexuses can be performed using the whole oesophagus and the isolated mucosal layer. 5. The use of the guinea-pig isolated vagus nerve-oesophagus preparation allows potency determinations for both neuromuscular and ganglion blockade of various non-depolarizing muscle relaxants to be performed simultaneously under identical conditions. Furthermore, the phenomenon of fade, a waning of tetanic tension during the stimulation period, can be studied. 6. A potential application of this preparation is the simultaneous screening of the constituents of snake venoms for activity at the neuromuscular junction and/or the ganglion. It is also suggested that new calcium channel blockers could be screened in this preparation because different voltage-sensitive calcium channels are involved in neurotransmitter release from nerve terminals at the neuromuscular junction and autonomic cholinergic neuroeffector sites.