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Biomedical subjects

D W Oliver

Publications and source records attributed to D W Oliver.

At least 37 records · Page 2Linked to original sources
PubMed2000

Stability and partitioning of closantel and rafoxanide in ruminal fluid of sheep.

The stability and the partitioning of closantel and rafoxanide in ruminal fluid (RF) was examined in vitro. Stability was evaluated in two studies in a ruminal fluid-artificial saliva (RF-AS) mixture containing either drug. Drug concentrations were measured in samples collected sequentially from four batches of RF-AS fortified with either closantel or rafoxanide in one study and in four separately incubated aliquots of a RF-AS mixture of each drug in the second study at the start and at various intervals during a 24 h incubation period. The viability of the in vitro RF-AS incubation model was validated by the presence of digoxin degradation (T1/2 of 39,1 +/- 13 h) and by the absence of significant time related differences (P> 0,5) in volume of gas produced, pH and methylene blue reduction time of the RF-AS drug mixture. Partitioning of closantel and rafoxanide was determined by measuring the relative drug concentration of the fluid and particulate phases in RF fortified with either drug at different concentrations. Closantel and rafoxanide were shown to be stable in a RF-AS mixture and were not subjected to any significant biodegradation. An initial marked reduction in drug concentration measured in the RF-AS mixture during the first 2 h of incubation was attributed to the attachment of both drugs onto particulate matter. This was subsequently confirmed in the partitioning study. More than 80% of closantel and rafoxanide was shown to be associated with the particulate phase of RF

Animals↗
PubMed1999

Pharmacological effects of Agapanthus africanus on the isolated rat uterus.

The Agapanthus africanus plant is used by South African traditional healers as a phytomedicine in herbal remedies to treat pregnancy-related ailments and to augment labour. It has already been shown that an aqueous extract of A. africanus causes smooth muscle contractions in the isolated uterus and ileum preparations. In the present study, the effects of an aqueous extract of A. africanus leaves was examined on receptor systems involved in contraction of the uterine smooth muscle in order to determine the mechanism of its pharmacological effect relevant to its ethnic use to augment labour. The extract was tested on the isolated rat uterus preparation. The aqueous extract of A. africanus leaves was found to exhibit agonist activity on uterine muscarinic receptors and to promote the synthesis of prostaglandins in the oestrogenized rat uterus. Some pharmacological justification for the ethnic use of A. africanus as a herbal oxytocic in prolonged labour has been provided.

Acetylcholine↗
PubMed1999

Massive plexiform neurofibroma of the sympathetic trunk.

A case report of a massive plexiform neurofibroma of the sympathetic trunk is reported. Symptoms included dysphagia, shortness of breath and paraesthesia of the right hand. The nerve of origin and extent of the tumour were unusual. The tumour mass partially filled the right hemithorax, surrounded the right brachial plexus, extended to the base of skull and invaded the cervical vertebrae threatening to compromise the spinal cord. Surgical resection required combined cardiothoracic, neurosurgical and plastic and reconstructive surgical teams. Early outcome following surgery was excellent. This case illustrates the need for a combined surgical approach for such a lesion and we believe it is the first reported case of plexiform neurofibroma of the sympathetic trunk.

Female↗
PubMed1999

Cerebral blood flow effects of the nitric oxide donor, nitroglycerin and its drug combinations in the non-human primate model.

Nitroglycerin (CAS 55-63-0, Nitrocene) has successfully been used in the management of angina during the last several decades. Although important information on the pharmacological actions and efficacy of nitroglycerin have been extracted, to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur under treatment of a wide variet of drugs. Illucidation of the pharmacological mode of action of nitroglycerin has gained momentum with the discovery of nitric oxide (NO) as an endogenous mediator and with the knowledge that nitroglycerin acts as a NO donor. The present study investigated the effects of nitroglycerin (0.25 microgram/kg/min over 10 min) on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amine oxime) and SPECT, in an anaesthetised primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The present study with nitroglycerin indicates that the response time to measure cerebral blood flow effects seems to be present and an important factor as the transient is relatively short. The current treatment regime with nitroglycerin indicates a slight increase, when compared with control control results, although not significant, except for regional significant increases in particular the occipital regions of the brain. Drug interaction between nitroglycerin and nimodipine may occur as a reduction of 20% in cerebral blood flow from the control control was observed in this case. The results for the combination of nitroglycerin with sumatriptan showed a further increase of the cerebral blood flow to near significance, when compared with the control results and is significantly increased (+27%) when compared with sumatriptan treatment alone. Effective treatment with sumatriptan may therefore be compromised with simultaneous administration of nitroglycerin or NO donor drugs. The combination of nitroglycerin and acetazolamide suggested that the increase in cerebral blood flow is primarily attributed to the influence of acetazolamide. The cerebral blood flow effects of these drugs and possible interactions during an angina attack need to be investigated.

Acetazolamide↗
PubMed1999

SPECT monitoring of improved cerebral blood flow during long-term treatment of elderly patients with nootropic drugs.

PURPOSE: In normal aging persons, oxygen and glucose consumption progressively decreases with reduced cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A data processing model with the use of Tc-99m SPECT of the human brain has been developed and found to be sensitive for monitoring the effects of drugs that increase CBF. In this study, the effect of two vasodilator drugs (the combination of pentifylline and nicotinic acid versus piracetam) was compared with the effect of placebo on CBF. MATERIALS AND METHODS: Thirty elderly volunteers had three different procedures using the Peelproc method to spatially standardize and compare CBF patterns by SPECT before and after drug intervention. The 30 patients were divided into five groups of six persons each who were randomly assigned in a 1:1 ratio to the treatment sequences consisting of three phases: the combination of pentifylline and nicotinic acid (C), piracetam (N), and placebo (P), or C-N-P; P-N-C; P-C-N; N-C-P; C-P-N; or N-P-C. Phases 1 to 3 each consisted of a baseline recording of parameters (day 0), treatment for 60 days (days 1 to 60), and recording of parameters after treatment (day 61). RESULTS: In elderly human volunteers (ages, 52 to 70 years), after 2 months of oral treatment with a combination of pentifylline and nicotinic acid (800 mg pentifylline, 200 mg nicotinic acid daily), SPECT results for the Peel-proc program indicated a statistically significant improvement in CBF of the total brain, with a more pronounced improvement in the cerebellum and frontal regions, where a definite shift from abnormal to normal blood flow was detected. Spontaneous communication from most of the volunteers suggested that they experienced an improvement in memory and general well-being from the combination treatment. After 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT results indicated a regional improvement in CBF, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. CONCLUSION: The in vivo method to quantitatively monitor the progress of long-term drug therapy on CBF described here could be useful to assess and even direct changes in therapy.

Administration, Oral↗
PubMed1998

Characterization of the enzymatic activity for biphasic competition by guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) at alpha2-adrenoceptors. I. Description of an enzymatic activity in spleen membranes.

The mechanism for formation of high-affinity binding of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine (guanoxabenz) to alpha2-adrenoceptors was studied in particulate fractions from the rat spleen. The proportion of apparent high versus low-affinity alpha2-adrenoceptor binding sites increased with increasing incubation time and was also augmented by Mg2+ ions. The formation of high-affinity guanoxabenz binding seemed to be inhibited by a series of N-hydroxyguanidine analogs to guanoxabenz, as well as by a series of metabolic inhibitors that included allopurinol, 1-chloro-2,4-dinitrobenzene, 5,5'-dithiobis-(2-nitrobenzoic acid), cibacron blue, phenyl-p-benzoquinone, didox, and trimidox. The formation of guanoxabenz high-affinity binding was also inhibited in a time- and concentration-dependent fashion by preincubating the membranes with the LW03 N-hydroxyguanidine analogue of guanoxabenz. Moreover, when the spleen membranes were extensively washed for 30 min with buffers at 25 degrees, the guanoxabenz high-affinity binding disappeared. However, when these washed membranes were supplemented with xanthine, the apparent affinity of guanoxabenz increased four to five-fold. Taken together, all data were compatible with the theory that the formation of high-affinity binding was dependent on the generation of a guanoxabenz metabolite that showed an approximate 100-fold greater affinity for the alpha2-adrenoceptors than guanoxabenz itself. Because the most potent blocker of the formation of high-affinity binding was allopurinol (apart from some N-hydroxyguanidine analogs to guanoxabenz) and since the activity could be restored with xanthine, a likely candidate responsible for the metabolic activation is xanthine oxidase.

Animals↗
PubMed1998

Patient satisfaction and symptom relief after anal dilatation.

Anal dilatation is used as a simple method of treatment and has been used for both anal fissure and haemorrhoids. This study examined longer-term results among a cohort of 162 patients, 132 of whom responded to a detailed questionnaire, an 82% response (66 patients were male; age range 17-75 years, median 42 years). Follow-up ranged from 16 months to 36 months (median 27 months) after anal dilatation (68 patients for fissure, 32 for haemorrhoids, and 32 for both). In the early months after dilatation, 83% had symptomatic improvement and 76% remained improved. Five (7%) patients with fissure and 11 with haemorrhoids (17%) required further hospital treatment, while 10% and 17%, respectively, had received further treatment from their general practitioners (GPs). Seventy-one percent said they would have a further anal dilation if symptoms recurred. There was no difference in results obtained by surgeons of different seniority. Complications--bleeding (29%) and difficulty controlling flatus (15%) or faeces (8%)--resolved in all cases. The results of anal dilatation for fissure are generally satisfactory in the longer term, with a trend toward better symptom relief in patients with fissure compared with those with haemorrhoids. We do not recommend anal dilatation as the sole treatment of patients with haemorrhoids, but it may be a useful adjunct to other treatments such as banding or sclerotherapy. Morbidity was generally acceptable and the majority of our patients would be prepared to have this procedure again if their symptoms were to return.

Adolescent↗
PubMed1998

Cerebral blood flow effects of sodium valproate in drug combinations in the baboon model.

Sodium valproate (CAS 1069-66-5, Epilim) has been used in the management of epilepsy during the last three decades. Although important information on the pharmacological actions and efficacy of sodium valproate has accrued to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur in epileptic patients. Furthermore it was established recently that sodium valproate influences the cerebral blood flow in children by decreasing the flow significantly. The present study investigated the effects of sodium valproate on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amino oxime) and SPECT, in a primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The current study using single dose treatment with sodium valproate did not detect a decrease or increase of the cerebral blood flow when compared with control baseline results. Drug interaction between sodium valproate and nimodipine may occur as a reduction of 25% in cerebral blood flow from the baseline control was observed in this case. The effects observed for the combinations of sodium valproate respectively with sumatriptan and acetazolamide are attributed to the influences of the sumatriptan (decrease) and acetazolamide (increase) alone. The cerebral blood flow effects of these drugs and possible interactions during an acute epileptic seizure need to be investigated.

Acetazolamide↗
PubMed1997

Effect of the haloperidol tetrahydropyridine metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine on dopamine receptor and transporter binding. A nonhuman primate 123I-iodobenzamide and 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane single photon emission computed tomographic study.

Researching the biological activities and toxicities of metabolites of drugs is of growing importance and has received increasing attention during the last decade in order to gain a better understanding of the efficacy and safety profile of drugs in clinical use. HPTP (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3, 6-tetrahydropyridine, CAS 52669-92-8), the tetrahydropyridine metabolite of the classical neuroleptic, haloperidol (CAS 52-86-8), has recently been the focus for further understanding the well-known side effect profile of haloperidol. The current study was aimed at investigating the effect of HPTP treatment on dopamine receptor and transporter binding in the nonhuman primate, i.e. the baboon Papio ursinus. The study was performed using the dopamine receptor ligand, 123-I-iodobenzamide (IBZM) and the dopamine transporter ligand, [123]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) in planar scintigraphy and single photon emission computed tomographic (SPECT) protocols. Dopamine receptor binding in the striatum was measured from the time activity curves by calculating the IBZM ratios of the basal ganglia to frontal cortex and of the basal ganglia to cerebellum. 99mTc-HMPAO (hexamethylpropylene amine oxime) SPECT detected no changes in striatal perfusion during HPTP treatment. The transporter binding was measured by dynamic imaging of the basal ganglia, frontal cortex and cerebellum using beta-CIT. IBZM dopamine receptor binding is initially (as measured after 18 weeks treatment) decreased by HPTP treatment in the basal ganglia, frontal cortex (not significantly) and cerebellum but reversed to control values in the frontal cortex, as measured after 58 weeks treatment with HPTP. The binding to the basal ganglia and to a lesser degree the cerebellum is still affected after 58 weeks treatment with HPTP but indicates a tendency to return towards the control values. The results of the planar dynamic study with beta-CIT indicate a decrease in the beta-CIT binding to the dopamine transporters in the basal ganglia and to a lesser extent the cerebellum as measured by the time activity and percentage washout rate of the beta-CIT in the HPTP treated baboons. The effect of HPTP on the serotonin transporters appears to be minimal as observed from the results obtained from the frontal cortex. These results indicate that HPTP treatment influences both presynaptic and postsynaptic neurofunction in the dopaminergic neurones.

Animals↗
PubMed1997

Technetium-99m-HMPAO, technetium-99m-ECD and iodine-123-IMP cerebral blood flow measurements with pharmacological interventions in primates.

UNLABELLED: Technetium-99m-bicisate ethyl cysteinate dimer (ECD) presents a different pattern from cerebral blood flow (CBF) in the subacute phase of cerebral infarction, as measured by PET, perhaps due to lack of oxygen and enzyme activity; this pattern is contrary to that of hexamethyl-propyleneamine oxime (HMPAO) but similar to that of N-isopropyl-[123I]beta-iodoamphetamine ([123I]IMP). This study explores possible CBF differences among HMPAO, ECD and IMP, with various relevant drug interventions. METHODS: Anesthetized adult baboons were used in these SPECT studies. Four studies (n = 6 baboons for each study), one control study and three intervention studies involving intravenous acetazolamide, nimodipine infusion and intramuscular sumatriptan, were followed with 99mTc-HMPAO, 99mTc-ECD and [123I]IMP. The split-dose method was used as follows. For each tracer, intervention data from the second SPECT (SPECT-2) after the second tracer injection (444 MBq) reflected a change in CBF with respect to the baseline SPECT (SPECT-1) data from the initial injection (222 MBq). These changes as a ratio, R (R = SPECT-2/SPECT-1), for each study, and the R values for each tracer were compared to R values from the corresponding control studies, yielding a quantitative estimate of drug effects. RESULTS: There were no significant differences (p > 0.05) between HMPAO and ECD for the control, acetazolamide and sumatriptan studies, but there was indeed a difference between the two for the nimodipine study, indicating a nimodipine-dependent underestimation of CBF with ECD (and also with IMP), with respect to HMPAO. A further significant difference was that larger CBF increases were observed with acetazolamide, as measured with [123I]IMP. CONCLUSION: This is a crucial observation for the clinical interpretation of CBF SPECT data and should direct the choice of tracer for a specific examination.

Acetazolamide↗
PubMed1996

Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study.

Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyrid ine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 99mTc-HMPAO (hexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the IBZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.

Animals↗
PubMed1996

Dopamine receptor binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)- 4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP), an intermediate metabolite of haloperidol.

The neuroleptic agent haloperidol (HP) is biotransformed to metabolites such as 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP) and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium (HPP+). In this study, radioligand binding studies were performed using [3H]SCH23390 as a dopamine D1 receptor ligand and [3H]spiperone as a D2 ligand. Ki values for D1 receptors were 35.8 microM and 54.9 microM for HP and HPTP, respectively. Corresponding values for D2 receptors were 39.1 nM and 329.8 nM. These results indicate similar low affinities in the micromolar range for both HP and HPTP at the dopamine D1 receptor, a much higher affinity of both HP and HPTP for the D2 receptor than for the D1 receptor, and that HPTP binds to D2 receptors with a 9-fold lower affinity than HP. The data are consistent with observations in mice that HPTP is a much less potent acute neuroleptic agent than HP.

Animals↗
PubMed1996

Cerebral blood flow effects of piracetam, pentifylline, and nicotinic acid in the baboon model compared with the known effect of acetazolamide.

In normal aging humans there is a progressive decrease of oxygen and glucose consumption with a reduction of cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A baboon model under anaesthesia using single photon emission computed tomography (SPECT) of the brain and the radiopharmaceutical hexamethylpropylene amine oxime (99mTc-HMPAO) has been developed and found to be sensitive to the effects of drugs that are known to increase CBF. In the present study, the effect of two haemorrheologically active drugs, viz a combination of pentifylline (CAS 1028-33-7) and nicotinic acid (CAS 59-67-6) vs. piracetam (CAS 7491-74-9) were compared with the known effect of acetazolamide (CAS 59-66-5) on CBF in the baboon model using the 99mTc-HMPAO split dose method. Acetazolamide (p < 0.05) and the combination of pentifylline and nicotinic acid (p < 0.01) increased the CBF when compared with the control baseline. The CBF was not significantly increased upon treatment with piracetam, pentifylline alone and nicotinic acid alone, when compared with the control values for total brain ratios (p > 0.05). However, an increased regional effect was observed for piracetam. These results indicate that the above haemorrheologically active drugs exhibit specific but different effects on cerebral blood flow with possible clinical implications.

Acetazolamide↗
PubMed1995

A comparative cerebral blood flow study in a baboon model with acetazolamide provocation: 99mTc-HMPAO vs 123I(IMP).

Pharmacological interactions are important when nuclear medical procedures are applied to patients under drug therapy, or drug provocation. This study compares in baboon models (regional) cerebral blood flow [(r)CBF] results from 99mTc-HMPAO and 123I-iodoamphetamine [123I(IMP)] each with and without acetazolamide, the latter a suggested drug for testing cerebrovascular reserve. Expected differences in cerebral uptake were observed between the two radio-tracers without acetazolamide. The increase in tracer uptake resulting from acetazolamide is significantly enhanced for 123I(IMP), which could have diagnostic implications.

Acetazolamide↗
PubMed1995

Cerebral blood flow effects of sumatriptan in drug combinations in the baboon model.

Sumatriptan (CAS 103628-46-2, Imigran) has established itself as an important therapeutic agent in the treatment of migraine. Although considerable understanding of, in particular, the vascular pathophysiology of migraine has been gained during the past decade, the pathophysiology and mediators involved in the pain experience during migraine ar during migraine are not yet fully explained. The mechanisms behind the pharmacological effects of sumatriptan are still only partially understood. In the present study the effects of sumatriptan on drug induced cerebral blood flow increases in the baboon model were investigated using 99mTc-HMPAO (hexamethylpropylene amine oxime) and SPECT (single photon emission computed tomography). Sumatriptan selectively reduced drug induced cerebral blood flow increases. The effects of halothane anaesthesia and acetazolamide on cerebral blood flow were not reversed by sumatriptan, while the effect of nimodipine was attenuated by 47% (to the level of cerebral blood flow below the normal flow baseline). These results support multiple mechanisms for sumatriptan involving vascular neurotransmission and neurogenic inflammatory responses via serotonin receptor stimulation and Ca2+ mobilization. Drug-drug interactions are further implicated through this study.

Acetazolamide↗