Biomedical subjects

Robert J Morgan

Publications and source records attributed to Robert J Morgan.

24 records · Page 2Linked to original sources

PubMed2003

Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies.

PURPOSE: Azidothymidine (AZT, zidovudine) has been shown to reverse cisplatin resistance in cell culture. This phase I study was performed to determine the maximally tolerated dose (MTD) and dose-limiting toxicities of AZT when administered by continuous intravenous infusion in combination with cisplatin (CDDP), and to evaluate the pharmacokinetics of AZT in this setting. PATIENTS AND METHODS: Entered in the study were 61 patients with advanced, histologically confirmed malignancies which were unresponsive to or for which no "standard" chemotherapeutic regimen existed. AZT was administered as a 72-h infusion on days 1-3 and 14-16 of a 28-day cycle at dose levels from 400 through 14,364 mg/m(2) per day. CDDP at dose levels of 30, 45, or 60 mg/m(2) was administered at hour 36 of each AZT infusion. The plasma pharmacokinetics of AZT were determined in patients treated at representative dose levels. RESULTS: Of the 61 patients who completed 125 courses of therapy, 21 had stable disease for a median of four cycles (range two to eight), 33 progressed on therapy, and 7 were not assessable for response. The major observed toxicity was myelosuppression. The MTD of AZT was 8135 mg/m(2) per day when administered on this schedule. Escalation of CDDP did not result in additive toxicity. The mean steady-state level of AZT at the MTD was 44 microM (range 35-51 microM). CONCLUSIONS: Steady-state concentrations of AZT increased with dose. The plasma levels achieved at the MTD exceeded those required for drug resistance reversal in vitro. The administration of CDDP had no effect on AZT steady-state levels. The dose-limiting toxicity of this drug combination is myelosuppression. AZT may be useful in further studies utilizing combination therapy to achieve increased chemotherapy effectiveness.

Adult↗

PubMed2002

Decreased urinary bladder apoptosis in a rabbit model of diabetes mellitus.

Urinary bladder dysfunction is a recognised complication of diabetes mellitus (DM). This is thought to be partly related to altered bladder morphology as DM is associated with increased bladder weight. In DM, increased cellular proliferation is well established. However, there is evidence that in other pathological states affecting the urinary tract, altered apoptosis may also play a role. We therefore used a rabbit model to investigate whether there are any changes in bladder apoptosis with DM. Diabetes was induced in adult New Zealand white rabbits. Age-matched controls were also used. After 6 months, the bladders were excised and weighed. The TUNEL technique was used to detect and quantify apoptosis in both DM and age-matched control bladders. Diabetes was confirmed as this group had significantly (P<0.001) elevated serum glucose-compared to controls. The bladder weights were also significantly (P<0.001) greater in the DM rabbits. Apoptosis was significantly (P<0.001) decreased in the urothelial cells of the DM bladders. Our results confirm previous findings that DM is associated with increased bladder weight. Although this is associated with increased cellular proliferation, we have demonstrated that decreased apoptosis may also play an important role. Therefore, decreased apoptosis may be important in the pathophysiology of DM cystopathy.

Animals↗

PubMed2002

Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl.

Endothelin-1 (ET-1) causes urinary bladder smooth muscle contraction and the endothelin receptors A and B (ET(A) and ET(B)) are both known to be present in the rabbit urinary bladder. Alterations in ET-1 signalling have been implicated in the pathophysiology of urinary tract disorders secondary to bladder outlet obstruction and also in diabetic cystopathy. Naftidrofuryl (Naf) (marketed under the trade name Praxilene) improves walking distance in patients with peripheral vascular disease, an effect which may be partially attributed to ET-1 antagonism. The purpose of this study is to assess whether Naf will reduce ET-1 binding in the rabbit detrusor muscle and to assess whether there is inhibition of ET-1-mediated detrusor contraction. Detrusor smooth muscle strips were mounted in organ baths and cumulative response curves were measured for ET-1-mediated contractions in the presence and absence of 10(-6) M Naf (therapeutic concentration). In addition, ET-1 was added to the detrusor strips in the presence of the ET(A) antagonist, BQ123, and the ET(B) antagonist, BQ788, to identify the receptor subtype functionally involved. Overall inhibition of [(125)I]ET-1 binding by Naf was assessed using autoradiography. Identification of receptor-subtype binding reduction was assessed using the radioligands [(125)I]PD151242 and [(125)I]BQ3020. Naf inhibited ET-1-mediated detrusor contractions significantly (P<0.04), e.g. at 10(-10) M ET-1, contraction was completely abolished by Naf. Autoradiography indicated that Naf competitively inhibited [(125)I]ET-1 binding in a dose-dependent manner (IC(50)=3x10(-7) M). All radioligand binding was reduced indicating binding of Naf to both ET(A) and ET(B) receptors. Naf reduces binding of ET-1 to rabbit detrusor ET(A) and ET(B) receptors and inhibits ET-1-induced detrusor contractions mediated by ET(A) receptors. Naf may have therapeutic potential in the treatment of bladder disorders secondary to bladder outlet obstruction and diabetes mellitus.

Animals↗

PubMed2002

The choice of antihypertensive drugs in patients with erectile dysfunction.

It is well established that hypertension and the more traditional anti-hypertensive drugs are associated with erectile dysfunction (ED). There is evidence showing that two antihypertensive drugs--doxazosin and losartan--have a positive effect on erectile function. Therefore these drugs may decrease the incidence of ED in patients who need treatment for hypertension. Doxazosin and/or losartan can also be beneficial in patients who develop ED after starting treatment with other antihypertensive drugs. These options could, in turn, ensure better compliance and blood pressure control. A fall in the overall cost of treatment will also be anticipated if there is a reduced need for drugs prescribed for ED in patients with hypertension.

Aged↗

PubMedDate not supplied

Immunocytochemical and pharmacological characterisation of P2-purinoceptor-mediated cell growth and death in PC-3 hormone refractory prostate cancer cells.

BACKGROUND: Extracellular nucleotides (e.g adenosine 5'-triphosphate, ATP) influence biological processes via purinergic receptors. We characterised the P2-purinoreceptors in human hormone refractory prostate cancer (HRPC) cells (PC-3 cells). RESULTS: 1. Immunofluorescent staining demonstrated P2X3 P2X, P2X5 P2X7 and P2Y2 receptors. 2. ATP inhibited cell growth by up to 91% over 72h. Pharmacological characterisation indicated a P2X-purinoreceptor-mediated response. 3. Comparable maximum growth inhibition was seen after either a single addition of 1mM or daily addition of 100mM ATP. ATP concentrations ([ATP]) returned to baseline levels within 24h if the initial [ATP] was < or =100 HM, while [ATP] remained high for 72h if a single concentration of 1 mM was used. 4. ATP 1 mM significantly (p<0.001) increased the proportion of cells undergoing apoptosis from 0.27% (+/- 0.04%) to 5.28% (+/- 0.77%). CONCLUSION: Threshold concentrations of ATP inhibited HRPC cell growth in vitro via the activation of P2X-purinoreceptors. The role of nucleotides in the treatment of HRPC requires further investigation.

Adenosine Triphosphate↗

PubMedDate not supplied

Pharmacological properties of endothelin-1 in the rabbit corpus cavernosum.

BACKGROUND: Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusively demonstrated. Augmented cavernosal smooth muscle (CSM) contraction in the rat occurs following exposure to both ET-1 and phenylephrine (PE; alpha-1 agonist). The aim of this study was to assess the effect of ET-1 and its possible role in the alpha1-adrenergic pathway during the erectile process. MATERIALS AND METHODS: Organ bath studies were performed on CSM strips of penises obtained from 12 age-matched New Zealand White rabbits. The effect of ET-1 and PE alone on CSM tone in the absence and presence of ETA (BQ123) and ETB (BQ788) antagonists was assessed. Tissue responses were measured as tension (newton, N). EC50 values are expressed as mean +/- S.E.M. RESULTS: PE (10(8) - 10(-4) M) and ET-1 (10(-10) - 10(-6) M) produced a concentration-dependent contraction in rabbit CSM strips. The EC50 values were 1.7 x 10(-7) M +/- 1.1 and 3.4 x 10(-9) M +/- 1.5, respectively. BQ123 10(-5) M significantly inhibited ET-1-mediated CSM contractions more than BQ788 10(-5) M (both ANOVA p<0.01). The EC50 were 1.3 x 10(-6) M +/- 2.6 and 2.0 x 10(-7) M +/- 2.1, respectively. Neither the ETA or ETB receptor antagonist had a significant influence on alpha1-adrenergic receptor-mediated CSM contraction. CONCLUSION: ETA receptors may play a greater role than ETB receptors in ET-1-induced rabbit CSM contraction and the detumescence process. The a1-adrenergic-dependent pathway does not involve the ETA or ETB receptors.

Adrenergic alpha-Agonists↗