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Biomedical subjects

C J Fowler

Publications and source records attributed to C J Fowler.

At least 109 records · Page 6Linked to original sources
PubMed1997

Simultaneous arterial and urinary bladder pressure recordings in multiple system atrophy and in spinal disorders with detrusor hyperreflexia.

Simultaneous arterial and urinary bladder pressure measurements were recorded during bladder filling in 21 patients with urinary bladder symptoms; seven patients had autonomic failure due to multiple system atrophy (MSA), seven had spinal cord disease of different aetiology with detrusor hyperreflexia (DH) and seven had no neurological abnormalities. A significant increase in average systolic blood pressure (BP) was recorded on bladder filling in the neurologically intact patients (from 110 to 137 mmHg) and in the patients with spinal cord disease and DH (from 109 to 129 mmHg). In those with MSA, the BP rose in four and fell in three patients. The vesicopressor response during cold receptor-mediated DH was not significantly higher when compared with room-temperature saline and when compared with the BP response during bladder filling in the neurologically intact patients. Finally, intravesical lignocaine retained in the bladder for 15 min did not influence the BP response to cold receptor stimulation in patients with spinal cord disease and DH. These findings and their pathophysiological and clinical implications are discussed.

Adult↗
PubMed1997

Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study with long-term followup.

PURPOSE: We described the long-term outcome of intravesical capsaicin instillations in patients with urinary incontinence and compared its efficacy in 2 similar populations of patients with multiple sclerosis in a dual center study. MATERIALS AND METHODS: During 5 years 79 patients with intractable urinary incontinence have been treated with intravesical capsaicin. The majority of patients had spinal cord disease due to multiple sclerosis but 4 were neurologically normal. Cystometry was performed before and 4 to 6 weeks after intravesical instillation of 1 to 2 mmol./l. of capsaicin in 30% ethanol in saline. Instillations of vehicle (30% ethanol in saline) alone were carried out in 5 patients. RESULTS: In patients with phasic detrusor hyperreflexia complete continence was achieved in 44%, satisfactory improvement occurred in 36% and treatment failed in 20%. Clinical benefit from a single instillation lasted 3 to 6 months and was repeated in some patients with similar improvement. Capsaicin was ineffective in patients with poor bladder compliance and in neurologically normal patients with sensory urgency and detrusor instability. There was no clinical or urodynamic improvement in patients treated with vehicle alone. There have been no long-term complications. CONCLUSIONS: Our study shows that repeated instillations of intravesical capsaicin are effective in treatment of patients with detrusor hyperreflexia due to spinal cord disease and that effectiveness of the treatment persists at least 3 to 5 years.

Administration, Intravesical↗
PubMed1997

The role of the phosphoinositide signalling system in the pathogenesis of sporadic Alzheimer's disease: a hypothesis.

Great advances have been made in recent years in our knowledge of the genetic mutations found in early onset familial Alzheimer's disease (AD) and their pathological consequences. The pathogenesis of sporadic AD, on the other hand, is less clear, although a central role of oxidative stress is indicated. In the AD brain, severe dysfunctions in the phosphoinositide signalling pathway have been reported. In view of the fact that (a) oxidative stress can adversely affect phosphoinositide breakdown and hence diacylglycerol-mediated activation of protein kinase C and (b) protein kinase C activation reduces the production of beta-amyloid peptide from amyloid precursor protein, it is possible that this represents a pathogenic pathway whereby oxidative stress can lead to amyloid deposition and the development of the disease.

Alzheimer Disease↗
PubMed1997

Comparison of the effects of a series of kappa-opioid receptor agonists upon sodium channel function in rat brain miniprisms.

The blockade of veratrine-stimulated phosphoinositide breakdown in rat cerebral cortical miniprisms has been used as a model of drug action on voltage-dependent sodium channels. The kappa-opioid agonists bremazocine, (+/-)- and (+)-trans-U-50488, U-62066 (spiradoline) and U-69593 inhibited the response to veratrine with IC50 values of 35, 13, 15, 9, and > 100 microM, respectively. Bremazocine, at concentrations inhibiting the response to veratrine, did not inhibit the phosphoinositide breakdown response to the sodium ionophore monensin, indicating the specificity of the assay for sodium channels. The inhibitory actions of bremazocine upon veratrine-stimulated phosphoinositide breakdown were not antagonised by naloxone. This study thus confirms previous data suggesting that the kappa-opioid receptor agonists can affect Na(+)-channel function in a manner unrelated to their actions at kappa-opioid receptors. However, for the compounds tested, such effects are only found at rather high concentrations of the compounds.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

The 'Queen Square bladder stimulator': a device for assisting emptying of the neurogenic bladder.

OBJECTIVE: To describe the effectiveness of a vibrating device for emptying the neurogenic bladder in patients with neurological disease. PATIENTS AND METHODS: The study involved 36 patients, comprising 29 with multiple sclerosis (MS), four with multiple system atrophy (MSA), one with radiation myelitis and two with neurological disease of uncertain aetiology. Most patients with MS (27) were able to walk unaided or with aids. Three of the 36 patients had loss of suprapubic sensation (two MS, one with uncertain diagnosis). All patients had free flow rates and ultrasonographic post-void residual volumes (PVRs) measured before and after voiding while using a vibrating device (frequency 60 Hz) applied to the suprapubic region. They also completed questionnaires about their urinary symptoms before and after the continued use of this device. The mean follow-up was 11.5 months (range 8-14). RESULTS: The device improved the symptoms in 25 of 36 patients (70%) and reduced the PVR from a mean (standard deviation) of 175 (78) mL to 68 (32) mL. It was not useful in patients with PVRs of > 400 mL, Kurtzke pyramidal function scores of > 3, and in those with suprapubic numbness. There were no complications and most patients complied well. CONCLUSIONS: Suprapubic vibration is an effective means of emptying the neurogenic bladder in patients who are not severely disabled and who have detrusor hyper-reflexia. It probably acts through a tonic vibration reflex which is under supraspinal influence. This device may be a useful alternative to clean intermittent self-catheterization.

Follow-Up Studies↗
PubMed1997

How to recognize patients with parkinsonism who should not have urological surgery.

OBJECTIVE: To examine whether there are urogenital criteria that the urologist could apply to a patient with idiopathic Parkinson's disease (IPD) and bladder symptoms, and so avoid operating on patients with multiple system atrophy (MSA). PATIENTS AND METHODS: The clinical features of 52 patients with probable MSA and 41 patients with IPD were studied retrospectively with particular attention to the nature of lower urinary tract symptoms and erectile dysfunction in relation to the onset of parkinsonism. Anal sphincter electromyography (EMG) was recorded in all the patients with MSA and in 12 of the patients with IPD. RESULTS: Of the patients with MSA, 60% had urinary symptoms preceding or presenting with IPD but in 94% of the patients with IPD the neurological diagnosis preceded the onset of urogenital symptoms. Most of the patients with MSA (73%) had troublesome urinary incontinence whereas the majority of those with IPD (85%) had urgency and frequency but were not incontinent; 66% of the patients with MSA and 16% of patients with IPD had a significant post-void residual volume. Of the men with MSA, 93% had erectile dysfunction and in 48% of them this complaint preceded the diagnosis of MSA. All 11 men with MSA who had a TURP were incontinent post-operatively. CONCLUSION: The urogenital criteria which favour a diagnosis of MSA are: (i) urinary symptoms preceding or presenting with parkinsonism; (ii) urinary incontinence and IPD; (iii) a significant post-void residual urine volume; (iv) erectile failure preceding or presenting with parkinsonism; and (v) worsening bladder control after urological surgery. Patients with parkinsonism and these features should be offered medical management rather than urological surgery.

Electromyography↗
PubMed1997

The ice-water test in detrusor hyper-reflexia and bladder instability.

OBJECTIVES: To determine: (i) the outcome of the ice-water test (IWT) in patients with an overactive detrusor and to define the sensitivity of the test in differentiating bladder instability from detrusor hyper-reflexia: and (ii) to investigate any differences in sensitivity to the IWT with detrusor hyper-reflexia caused by suprapontine and spinal pathologies. PATIENTS AND METHODS: Of 130 consecutive patients with urinary symptoms who underwent a urodynamic evaluation and IWT, 80 had detrusor overactivity; of these 60 had detrusor hyper-reflexia and 20 had bladder instability. The patients with detrusor hyper-reflexia were further subdivided into two groups, suprapontine or spinal, based on the site of the neurological lesion. RESULTS: The overall sensitivity of the test in patients with detrusor hyper-reflexia was 65% and the specificity 85%. In patients with a spinal pathology causing detrusor hyper-reflexia, the test was positive in 70%, while 46% with suprapontine causes of detrusor hyper-reflexia had a positive test. CONCLUSIONS: Although 65% of the patients with detrusor hyper-reflexia and known neurological disease had a positive IWT, so did 15% of the patients with no neurological disease and bladder instability. Patients with suprapontine pathology had a lower sensitivity than those with infrapontine pathology, but this was not statistically significant. The relatively larger number of false-negative tests in patients with a suprapontine pathology is one reason why the test is insufficiently sensitive to discriminate between detrusor hyper-reflexia and bladder instability.

Adolescent↗
PubMed1997

Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide.

A measure of the metabolism of anandamide, an endogenous cannabimimetic agent, by rat cerebellar membrane preparations was obtained by following the time-dependent reduction in potency of this compound towards inhibition of binding of the high-affinity cannabinoid agonist ligand [3H]WIN 55212-2 to cannabinoid receptors. Thus for example, incubation of the membranes with 100 nM anandamide for 0, 10 and 30 min. prior to addition of [3H]WIN 55212-2 and phenylmethylsulphonyl fluoride (to inhibit the activity of anandamide amidase, thereby blocking further anandamide metabolism during the binding assay) produced 57 +/- 3, 38 +/- 5 and 19 +/- 7% inhibition, respectively, of [3H]WIN 55212-2 binding. This time-dependent effect was blocked by ibuprofen but not by acetyl salicylic acid, sulindac, acetaminophen or to any significant extent by ketoprofen and naproxen. Preliminary experiments using a direct assay of anandamide amidase with [14C]anandamide as ligand gave an IC50 value for ibuprofen of approximately 400 microM. The potency of ibuprofen as an inhibitor of anandamide metabolism was of the same order of magnitude as required for inhibition of cyclooxygenase-2 in cell-free systems and of the peak plasma concentrations of this drug following a 2 x 200 mg dose regimen. It is concluded that following therapeutic doses of ibuprofen, the metabolism of anandamide may be affected.

Acetaminophen↗
PubMed1997

Alzheimer's, ageing and amyloid: an absurd allegory?

Recent research into the pathogenesis of Alzheimer's disease (AD) has focused upon the proposed neurotoxic role played by the beta-amyloid peptide. Other important neurochemical disturbances, such as the dramatic breakdown of intracellular signalling, should however not be overlooked. In the present article, the authors attempt to investigate the relationship between signalling disturbances and beta-amyloid and ask the question 'which came first?' The available evidence is discussed, and it is concluded that the need for a wide, rather than restricted, focus on biochemical events associated with AD is required if progress is to be made in the understanding and eventual treatment of this disease.

Aging↗
PubMed1997

The cause and management of bladder, sexual and bowel symptoms in multiple sclerosis.

Neurological control of bladder, bowel and sexual function depends on intact innervation between cerebral controlling centres and the conus of the cord. It is probably the spinal cord disease in multiple sclerosis (MS) which is the main cause of the pelvic organ dysfunctions that occur. Essential to bladder management is understanding to what extent the patient has incomplete emptying while complaining predominantly of symptoms of bladder overactivity. Anticholinergic medication can be highly effective for treatment of detrusor hyperreflexia but if incomplete emptying is also part of the problem intermittent catheterization or some other means of improving emptying will be necessary. Although there is an increasing range of treatments available for erectile failure there is still little that can be done to help women with sexual dysfunction. However, patients of both sexes are likely to welcome the opportunity to discuss their problem. The prevalence of bowel dysfunction is higher in patients with MS than in the general population and there are a number of possible pathophysiological mechanisms for both the constipation and the faecal incontinence that occur. However, there are as yet few specific effective treatments.

Female↗
PubMed1997

Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.

The ability of rat brain (minus cerebellum) homogenates to deamidate arachidonyl ethanolamide (anandamide) was determined with a custom-synthesized substrate, arachidonyl ethanolamide-[1-3H] ([3H]anandamide). Conditions whereby initial velocities were measured were established. The homogenates deamidated anandamide with a Km value of 0.8 microM and a Vmax value of 1.73 nmol . (mg protein)-1 . min-1. The deamidation of 2 microM -3H-anandamide was inhibited by phenylmethylsulfonyl fluoride and arachidonyl trifluoromethyl ketone with IC50 values of 3.7 and 0.23 microM, respectively. Ibuprofen inhibited anandamide deamidation in a mixed fashion, with Ki and K'i values of 82 and 1420 microM. At an anandamide concentration of 2 microM, the IC50 values (in microM) of a series of compounds related in structure to ibuprofen were as follows: suprofen, 170; ibuprofen, 270; fenoprofen, 480; naproxen, 550; ketoprofen, 650; diclofenac, approximately 1000. Sulindac produced 27% inhibition at a concentration of 1000 microM, whereas isobutyric acid, hydrocinnamic acid, acetylsalicylic acid and acetaminophen were essentially inactive at concentrations </= 1 mM. We conclude that ibuprofen inhibits anandamide deamidation at pharmacologically relevant concentrations and that there is some specificity to the inhibition produced by ibuprofen and suprofen.

Animals↗
PubMed1996

Receptor-effector coupling dysfunctions in Alzheimer's disease.

There is now good evidence that in the AD brain, a number of neurotransmitter effector systems are defective. Such abnormalities include defective G, protein and protein kinase C function as well as a drastically reduced level of receptors for the second messenger Ins(1,4,5) P3. Such changes are probably not restricted to the late stages of the disease, and are found in regions of the brain that show little histopathological abnormality, such as the cerebellum. Whether these changes precede or are secondary to primary histopathological changes such as beta-amyloid deposition is not as yet clear. What is clear, however, is that such signal transduction abnormalities are likely to negate therapeutic benefits in clinical strategies based upon the tenet of neurotransmitter replacement.

Alzheimer Disease↗
PubMed1996

Neurotransmitter receptor/G-protein mediated signal transduction in Alzheimer's disease brain.

Recent evidence suggests that the neurochemical pathology of Alzheimer's disease includes severe disruptions of the neurotransmitter receptor/G-protein mediated phosphatidylinositol hydrolysis and adenylyl cyclase signal transduction pathways. The present article briefly reviews evidence from postmortem studies describing disruptions to these systems and speculates as to the importance of these changes in terms of contributing to disease pathology and limiting the success of neurotransmitter replacement strategies.

Alzheimer Disease↗
PubMed1996

Urodynamic changes during therapeutic intravesical instillations of capsaicin.

OBJECTIVE: To describe the technique for and urodynamic changes during therapeutic instillations of intravesical capsaicin in patients with detrusor hyper-reflexia. PATIENTS AND METHODS: Ninety intravesical instillations of capsaicin were performed as a therapeutic procedure in 30 patients; 21 patients had various causes of non-traumatic spinal cord disease, five patients were very severely neurologically impaired and were bed-bound with an indwelling catheter, and four were neurologically normal. Simultaneous cystometry was performed in 25 patients during the instillation of capsaicin; 100 mL of 1 or 2 mmol/L capsaicin in 30% ethanol/saline was instilled into the bladder for 30 min and two patients received 30% ethanol/saline only. The last 56 capsaicin treatments were preceded by the instillation of 40 mL of 2% lignocaine for 20 min. Detrusor hyper-reflexia was decreased and urinary continence improved for 3-6 months after a single instillation; the instillation was then repeated. Two patients who received only ethanol/saline showed no clinical or urodynamic improvement. RESULTS: The treatment was not abandoned in any patient due to discomfort and there were no short- or medium-term complications. All patients with spinal cord disease and phasic detrusor hyper-reflexia had similar, frequent and repetitive detrusor contractions during the instillation of capsaicin. These acute reactive contractions did not occur in the neurologically normal patients. Similarly, the instillation of intravesical lignocaine only caused no phasic detrusor contractions. Intravesical lignocaine instillation before capsaicin markedly reduced and sometimes abolished the detrusor overactivity and lessened the discomfort for the patients. The instillation of lignocaine before capsaicin did not alter the benefit from each instillation of intravesical capsaicin. CONCLUSION: A method has been developed for administering capsaicin intravesically which diminishes discomfort for the patient and in the short- and medium-term is free of complications. The study also provides functional evidence of the role of capsaicin-sensitive afferents in phasic detrusor hyper-reflexia due to spinal cord disease.

Administration, Intravesical↗
PubMed1996

Neurotransmitters, signal transduction and second-messengers in Alzheimer's disease.

It has long been assumed that widespread changes in postsynaptic neurotransmitter receptor function are not a feature of the disrupted neurotransmission seen in the brains with Alzheimer's disease (AD). However, recent evidence from postmortem brain and fibroblast studies suggests that both the neurotransmitter receptor/G-protein-modulated adenylyl cyclase and the phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruptions may severely limit the functional integrity of key receptor types and undermine pharmacological attempts to ameliorate disease symptomatology through neurotransmitter replacement strategies. The involvement of some signalling mechanisms in the regulation of beta-amyloid precursor protein metabolism suggests also that disrupted signal transduction may exacerbate AD pathology.

Alzheimer Disease↗