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P F Smith

Publications and source records attributed to P F Smith.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Alkynes↗
PubMed2000

The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig.

Previous studies have demonstrated that vestibular compensation, the process of behavioural recovery which occurs following unilateral deafferentation of the vestibular labyrinth (UVD), is correlated with changes in in vitro phosphorylation of various protein substrates in the brainstem vestibular nucleus complex (VNC). The aim of the present study was to investigate the possible causal relationship between protein kinase activity and the induction of the vestibular compensation process, by delivering inhibitors of protein kinase C (PKC) or Ca(2+)/calmodulin-dependent kinase II (CaMKII) into the ipsilateral VNC at the time of the UVD and determining their effects on three static symptoms of UVD, spontaneous nystagmus (SN), yaw head tilt (YHT) and roll head tilt (RHT) in guinea pigs. Infusion of the PKC inhibitor, 3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrr ole-2,5-dione, HCl (bisindolylmaleimide I, HCl/GF 109203X, HCl) ('Bis I'), at a concentration of 5 or 50 microM, significantly increased SN frequency at the earliest time points (6 and 8 h post-UVD) compared to vehicle controls and the less selective analogue, 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (bisindolylmaleimide V) ('Bis V'). However, the compensation of YHT and RHT was unaffected by the PKC inhibitor. By contrast, the cell-permeable CaMKII inhibitor, myristoylated autocamtide-2 related inhibitory peptide (N-Myr-Lys-Lys-Ala-Leu-Arg-Arg-Gln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('myr-AIP') or the cell-impermeable analogue, autocamtide-2 related inhibitory peptide (N-Lys-Lys-Ala-Leu-Arg-Arg-Cln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('AIP'), failed to alter the compensation of SN, YHT or RHT at any dose compared to vehicle controls. These results implicate PKC-, but not CaMKII-, signal transduction pathways in the initiation of SN compensation in guinea pig.

Animals↗
PubMed2000

The effects of L-NAME on vestibular compensation and NOS activity in the vestibular nucleus, cerebellum and cortex of the guinea pig.

Nitric oxide (NO) has been implicated in the processes by which animals recover from peripheral vestibular damage ('vestibular compensation'). However, few data exist on the dose-response effects of systemic administration of the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on the vestibular compensation process. The aim of this study was to investigate the effects on compensation of 5, 10, 50 or 100 mM L-NAME administered by s.c osmotic minipump for 50 h following unilateral vestibular deafferentation (UVD) in guinea pig, either commencing the drug treatment at 4 h pre-UVD or at the time of the UVD (i.e., post-UVD). Post-UVD treatment with L-NAME, at any of the four concentrations used, had no effect on the compensation of spontaneous nystagmus (SN), yaw head tilt (YHT) or roll head tilt (RHT). By contrast, pre-UVD treatment with 100 mM L-NAME resulted in a significant decrease in SN frequency (P<0.05) and a change in the rate of its compensation (P<0.0005). Pre-UVD L-NAME resulted in a significant increase in the overall magnitude of YHT (P<0.005); however, post-hoc comparisons revealed no significant differences between any specific L-NAME and vehicle groups. Pre-UVD L-NAME had no effect on RHT at any concentration. Analysis of NOS activity in the pre-UVD L-NAME treatment groups at 50 h post-UVD showed that only 100 mM L-NAME resulted in a significant decrease in NOS activity in the contralateral medial vestibular nucleus (MVN)/prepositus hypoglossi (PH) (P<0.05) and that NOS activity in the ipsilateral MVN/PH was not significantly affected. However, NOS activity was significantly inhibited in the bilateral cerebellum and cortices for several concentrations of L-NAME. These results suggest that pre-UVD systemic administration of L-NAME can significantly increase the rate of SN compensation in guinea pig and that this effect is correlated with inhibition of NOS activity in several regions of the CNS.

Animals↗
PubMed2000

The effects of intra-vestibular nucleus administration of brain-derived neurotrophic factor (BDNF) on recovery from peripheral vestibular damage in guinea pig.

Brain-derived neurotrophic factor (BDNF), at doses of 0.04, 0.4 or 4.0 microg/day, was delivered by cannula and s.c osmotic minipump into the ipsilateral vestibular nucleus complex from 0 to 50 h following unilateral labyrinthectomy (UL) in guinea pigs. Compared to the vehicle control group, the frequency of spontaneous nystagmus was significantly reduced (p < 0.02) and the rate of yaw head tilt compensation increased (p < 0.02). However, roll head tilt was not signifcantly affected. There were also no significant effects of BDNF administration into the IVth ventricle (4.0 microg/day) on any UL symptom. These results further support the hypothesis that neurotrophins such as BDNF may enhance the vestibular compensation process.

Animals↗
PubMed2000

Vestibular nucleus N-methyl-D-aspartate receptors contribute to spontaneous nystagmus generation following unilateral labyrinthectomy in guinea pigs.

We investigated the effects of a non-competitive N-methyl-D-aspartate (NMDA) receptor/channel antagonist ((+)MK-801)) or an L-type Ca(2+) channel antagonist (nifedipine), delivered into the ipsilateral vestibular nucleus complex (VNC) before a unilateral labyrinthectomy (UL), on spontaneous nystagmus (SN) generation. Guinea pigs received either (+)MK-801 (5 or 12.5 microg); the less active enantiomer, (-)MK-801 (5 or 12.5 microg); nifedipine (5 or 10 microg); or vehicle, via cannula in the ipsilateral VNC. (+)MK-801, but not nifedipine, significantly decreased mean SN frequencies at 6 h post-UL, compared to controls (P<0.02) and reduced the rate of SN compensation (P<0.05). These results suggest that the SN expression is partly induced by NMDA receptor activation in the ipsilateral VNC at the time of the UL.

Animals↗
PubMed2000

Comparison of visual--vestibular interaction in insulin-dependent and non-insulin-dependent diabetes mellitus.

We compared various measures of visual-vestibular interaction in subjects with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM), as well as non-diabetic controls. Subjects with IDDM exhibited significantly greater postural sway than controls on those conditions in the Clinical Test of Sensory Interaction and Balance (CTSIB) which require greater reliance on the vestibular system (p < 0.005). The IDDM group also exhibited significantly worse gaze-holding in darkness and a significantly higher mean slow phase eye velocity (SPV) of optokinetic nystagmus (OKN; p<0.05 for both comparisons). However, there were no significant differences in latency to circularvection (CV). The NIDDM group showed a significant increase in postural sway across all 12 conditions compared with the controls, as well as a significant decrease in gaze-holding in darkness (p < 0.05 and p < 0.0005, respectively). However, they showed no significant difference in OKN SPV and a significant decrease in latency to CV for anticlockwise trials only (p < 0.05). These results suggest that IDDM and NIDDM are both associated with specific but different changes in visual-vestibular interaction.

Adult↗
PubMed2000

Effects of intra-vestibular nucleus injection of the group I metabotropic glutamate receptor antagonist AIDA on vestibular compensation in guinea pigs.

Removal of the peripheral vestibular receptor cells in one inner ear (unilateral vestibular deafferentation, UVD) results in a syndrome of ocular motor and postural disorders, many of which disappear over time in a process of behavioural recovery known as vestibular compensation. Excitatory amino acid receptors, in particular the N-methyl-D-aspartate (NMDA) receptor, have been implicated in vestibular compensation; however, the metabotropic glutamate receptors (mGluRs) have not been studied in this context. The aim of this study was to determine whether group I mGluRs in the brainstem vestibular nucleus complex (VNC) ipsilateral to the UVD are involved in vestibular compensation of the static symptoms of UVD in guinea pig. The selective group I mGluR antagonist (RS)-1-aminoindan-1,5,dicarboxylic acid (AIDA) was continuously infused into the ipsilateral VNC for 30-min pre-UVD and 30-min post-UVD by cannula, at a rate of 1 microl/h, using one of four doses: 0.1 fg, 0.1 pg, 0.1 ng or 0.1 microg (n=5 animals in each case). In control conditions, a 0.1-fg (n=4) or 0.1-microg (n=5) NaOH vehicle was infused into the ipsilateral VNC using the same protocol. In order to control for the possibility that AIDA disrupted spontaneous neuronal activity in the VNC in normal animals, 0.1 microg AIDA (n=4) or 0.1 microg NaOH (n=2) was infused into the VNC in labyrinthine-intact animals. In both groups, static symptoms of UVD (i.e. spontaneous nystagmus, SN, yaw head tilt, YHT and roll head tilt, RHT) were measured at 8, 10, 12, 15, 20, 25, 30, 35, 45 and 50 h post-UVD. In addition, the righting reflex latency (RRL) was measured in labyrinthine-intact animals in order to assess whether AIDA impaired motor coordination in labyrinthine-intact animals. In UVD animals, the highest dose of AIDA significantly reduced SN frequency and changed its rate of compensation (P<0.001 and P<0.0001, respectively). This dose of AIDA also caused a significant reduction in YHT (P<0.005) as well as a significant change in its rate of compensation (P<0.0001). However, RHT was not significantly affected. In the labyrinthine-intact animals, AIDA infusion did not induce a UVD syndrome, nor did it significantly affect RRL. These results suggest that group I mGluRs in the ipsilateral VNC may be involved in the expression of ocular motor and some postural symptoms following UVD. Furthermore, group I mGluRs may not contribute to the resting activity of vestibular nucleus neurons.

Adaptation, Physiological↗
PubMed2000

Molecular mechanisms of recovery from vestibular damage in mammals: recent advances.

The aim of this review is to summarise and critically evaluate studies of vestibular compensation published over the last 2 years, with emphasis on those concerned with the molecular mechanisms of this process of lesion-induced plasticity. Recent studies of vestibular compensation have confirmed and extended the previous findings that: (i) compensation of the static ocular motor and postural symptoms occurs relatively rapidly and completely compared to the dynamic symptoms, many of which either do not compensate substantially or else compensate variably due to sensory substitution and the development of sensori-motor strategies which suppress or minimize symptoms; (ii) static compensation is associated with, and may be at least partially caused by a substantial recovery of resting activity in the ipsilateral vestibular nucleus complex (VNC), which starts to develop very quickly following the unilateral vestibular deafferentation (UVD) but does not correlate perfectly with the development of some aspects of static compensation (e.g., postural compensation); and (iii) many complex biochemical changes are occurring in the VNC, cerebellum and even areas of the central nervous system like the hippocampus, following UVD. However, despite many recent studies which suggest the importance of excitatory amino acid receptors such as the N-methyl-D-aspartate receptor, expression of immediate early gene proteins, glucocorticoids, neurotrophins and nitric oxide in the vestibular compensation process, how these various factors are linked and which of them may have a causal relationship with the physiological changes underlying compensation, remains to be determined.

Animals↗
PubMed2000

Treating mammalian bite wounds.

The incidence of dog, cat and human bites has been increasing steadily and represents an important cause of morbidity and mortality in the United States. Approximately half of all Americans will suffer a bite wound during their lifetime, and the annual medical costs of managing these injuries has been estimated to be over $100 million. Possible complications may include disfigurement, dismemberment and infection. Effective management requires rapid medical evaluation and may necessitate surgical intervention and prophylactic antibiotic therapy. As bite wounds are microbiologically diverse and most often polymicrobial in nature, selection of an appropriate antibiotic regimen requires knowledge of common pathogens. Close clinical follow-up is recommended to minimize the risk of late complications.

Animals↗
PubMed2000

Consented testing of newborns and childbearing women for human immunodeficiency virus through a newborn metabolic screening program.

OBJECTIVE: In this program a postpartum woman could consent to receive her newborn's human immunodeficiency virus test result from the New York State Newborn Screening Program. STUDY DESIGN: By state regulation each postpartum woman was counseled and offered her newborn's human immunodeficiency virus test result. With the mother's consent, newborn human immunodeficiency virus antibody test results from the Newborn Screening Program were sent to the baby's pediatrician; otherwise, test results were blinded. Data were analyzed for births from August 1, 1996, to January 31, 1997. RESULTS: Overall, 92.5% of women offered newborn human immunodeficiency virus testing consented to receive the result. Among 444 human immunodeficiency virus-positive women offered newborn testing, consented testing resulted in a 21.4% increase in knowledge of human immunodeficiency virus status from 72.3% (n = 321) at delivery to 93.7% (n = 416) after newborn testing; 6.3% (n = 28) of human immunodeficiency virus-positive women delivered of infants who did not consent apparently remained unaware of their human immunodeficiency virus status. CONCLUSION: Combined prenatal and consented newborn testing identified 94% of human immunodeficiency virus-positive mothers and exposed newborns, allowing early entry into care. Such testing may provide an opportunity for women not previously tested for the human immunodeficiency virus to learn their status but is not a substitute for universal prenatal human immunodeficiency virus counseling and consented human immunodeficiency virus testing.

Adult↗
PubMed2000

Pharmacology of the vestibular system.

In the past year significant advances have been made in our understanding of the neurochemistry and neuropharmacology of the peripheral and central vestibular systems. The recognition of the central importance of excitatory amino acids and their receptors at the level of the hair cells, vestibular nerve and vestibular nucleus has progressed further, and the role of nitric oxide in relation to activation of the N-methyl-D-aspartate receptor subtype is becoming increasingly clear. Increasing evidence suggests that excessive N-methyl-D-aspartate receptor activation and nitric oxide production after exposure to aminoglycoside antibiotics is a critical part of hair cell death, and new pharmacological strategies for preventing aminoglycoside ototoxicity are emerging as a result. Conversely, the use of aminoglycosides to lesion the peripheral vestibular system in the treatment of Meniere's disease has been studied intensively. In the vestibular nucleus, new studies suggest the importance of opioid, nociceptin and glucocorticoid receptors in the control of vestibular reflex function. Finally, the mechanisms of action and optimal use of antihistamines in the treatment of vestibular disorders has also received a great deal of attention.

Animals↗
PubMed2000

Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males.

Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine, (-)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined. At least six subjects were studied at each dose level, with each subject studied in three of five periods, receiving two different doses of racemic dOTC and one placebo dose. Plasma and urine drug concentrations were measured for 24 to 48 h after each dose. Pharmacokinetic models were fitted to the plasma concentrations of (+)dOTC and (-)dOTC using maximum likelihood and maximum a posteriori Bayesian procedures. Statistical hypothesis testing was by nonparametric analysis of variance (where possible) and, when tests with dose as a covariate were performed, by linear mixed-effects modeling. The mean terminal elimination half-lives for (+)dOTC and (-)dOTC were 15.3 h (coefficient of variation [CV], 28%) and 11.3 h (CV, 43%), respectively (P<0.05). The mean CV for total oral clearance (liter/h/65 kg) was 17.5 (25%) for (+)dOTC and 21.5 (24%) for (-)dOTC; for oral steady-state volume of distribution (liter/65 kg), values were 61.8 (24%) for (+)dOTC and 34.1 (33%) for (-)dOTC (P<0.05). The mean CV for renal clearance (liter/h/65 kg) of (+)dOTC was 10.4 (19%) and for (-)dOTC was 13.6 (20%) (P<0.05). There was no significant effect of dose size on the pharmacokinetics of racemic dOTC. All doses were well tolerated, and no serious adverse events or laboratory abnormalities were observed.

Adolescent↗
PubMed2000

Absolute bioavailability and disposition of (-) and (+) 2'-deoxy- 3'-oxa-4'-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans.

The purpose of this study was to characterize the pharmacokinetics and determine the absolute bioavailability of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4'-thio heterosubstituted class of compounds and is a 1:1 mixture of its two enantiomers, (-) and (+) dOTC. Twelve healthy adult male volunteers each received oral (800-mg) and intravenous (100-mg) doses of dOTC in two study periods separated by at least 7 days. Sixteen plasma samples were obtained over 72 h and assayed for (-) and (+) dOTC, and the resultant data fit by candidate pharmacokinetic models. Data were weighted by the fitted inverse of the observation variance; model discrimination was by AIC. The pharmacokinetic model was a linear, three compartment model, with absorption occurring during one to three first-order input phases, each following a fitted lag time. The model goodness-of-fit was excellent; r(2) ranged from 0.995 to 1.0. The mean absolute bioavailabilities of (+) and (-) dOTC were 77.2% (coefficient of variation [given as a percentage] [CV%], 14) and 80.7% (CV%, 15), respectively. The median steady-state volume of distribution for (+) dOTC, 74.7 (CV%, 19.2) liters/65 kg, was greater than that for (-) dOTC, 51.7 (CV%, 16.7) liters/65 kg (P<0.05). The median total clearance of (+) dOTC was less than that of (-) dOTC, 11.7 (CV%, 17.3) versus 15.4 (CV%, 18.6) liters/h/65 kg, respectively (P< 0.05). The intersubject variability of these parameters was very low. The median terminal half-life of (+) dOTC was 18.0 (CV%, 31.5) h, significantly longer than the 6.8 (CV%, 69.9) h observed for (-) dOTC (P<0.01). No serious adverse events were reported during the study. These results suggest that dOTC is well absorbed, widely distributed, and well tolerated. The terminal half-lives indicate that dosing intervals of 12 to 24 h would be reasonable.

Administration, Oral↗
PubMed2000

Are vestibular hair cells excited to death by aminoglycoside antibiotics?

Aminoglycoside antibiotics are commonly prescribed throughout the world for the treatment of serious gram-negative bacterial infections. However, their use is limited by nephrotoxicity and ototoxicity. Although the traditional explanation for their ototoxicity in cochlear and vestibular hair cells has been the inhibition of mitochondrial protein synthesis, evidence is accumulating to suggest that many aminoglycosides cause excitotoxicity in hair cells as a result of their agonist action at the polyamine site on the N- methyl-D-aspartate (NMDA) receptor. The aim of this minireview is to summarise and critically evaluate this evidence and to consider the therapeutic implications of this hypothesis.

Aminoglycosides↗
PubMed2000

The effects of scopolamine and cyclizine on visual-vestibular interaction in humans.

The aim of the present study was to investigate the effects of scopolamine (1.5 mg, transdermal patch) and cyclizine (50 mg tablet), at the doses usually used for the relief of motion sickness, on postural sway, optokinetic nystagmus (OKN) and circularvection (CV) in humans, using a within-subjects, double-blind, placebo-controlled design. Scopolamine and cyclizine were found to have no significant suppressive effect on these aspects of visual-vestibular interaction. Postural sway and CV were not significantly affected by either drug treatment; OKN SPV was significantly increased (p < 0.05), although OKN amplitude and frequency were unaffected. These results suggest that scopolamine and cyclizine, at doses used for the relief of motion sickness, may have minimal suppressive effects on these aspects of visual-vestibular interaction.

Administration, Cutaneous↗
PubMed2000

Comparison of protein kinase activity and protein phosphorylation in the medial vestibular nucleus and prepositus hypoglossi in labyrinthine-intact and labyrinthectomized guinea pigs.

The aim of the present study was to compare in vitro protein expression, protein kinase activity and protein phosphorylation in the medial vestibular nucleus (MVN) and prepositus hypoglossi (PH) from labyrinthine-intact guinea pigs and from guinea pigs at various stages of vestibular compensation following unilateral labyrinthectomy (UL). The ipsilateral (I-MVN) and contralateral (C-MVN) MVN, and the ipsilateral (I-PH) and contralateral (C-PH) PH, were dissected from 3 naive labyrinthine-intact guinea pigs and 55 guinea pigs at 10 hs or 53 hs following a surgical UL or sham operation. Tissue extracts were incubated with [gamma-33P]ATP+/-Ca2+, phorbol 12, 13 dibutyrate and phosphatidylserine or +/- Ca2+ and calmodulin, to enhance protein kinase C (PKC) or calcium calmodulin kinase (CaMK) activity, respectively. Data were analysed as the ratio of activated to basal 33P incorporation detected by phosphorimaging. There were similar total protein and phosphoprotein profiles in the MVN and PH, as well as both PKC and CaMKII activity, suggesting that the MVN and PH are similar in the way that proteins undergo rapid modification by phosphorylation. During the development of vestibular compensation, a 46 kDa band in C-PH displayed higher PKC-mediated phosphorylation from 10 hs post-UL compared to sham controls. Significantly greater PKC-mediated phosphorylation of proteins of approximately 18, 46 and 75 kDa was observed in C-PH at 10 hs compared to 53 hs post-UL and in most cases the phosphorylation was greater in C-PH than in the C-MVN. These results suggest that between 10 and 53 hs post-UL, PKC-mediated phosphorylation changes mainly in the C-PH rather than the ipsilateral or contralateral MVN.

Animals↗
PubMed2000

The effects of repeated optokinetic stimulation on human autonomic function.

Numerous animal studies have suggested that the vestibular system modulates respiratory and cardiovascular function. However, relatively few studies have examined vestibular-autonomic interaction in humans. In this study we investigated the effects of repeated horizontal (clockwise or anticlockwise) optokinetic stimulation on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse and latency to circularvection (CV) in humans, and compared the effects with those of repeated exposure to a stationary visual stimulus. Although all subjects experienced CV, neither mean SBP, DBP or pulse differed significantly between the clockwise/anticlockwise optokinetic stimulation and no optokinetic stimulation conditions. However, SBP and DBP changed significantly over the 20 trials in each test session, even when there was no optokinetic stimulation (P < 0.001 in each case). These results suggest that while horizontal optokinetic stimulation does not significantly affect SBP, DBP or pulse in humans, changes in these variables can be induced by trial repetition itself, even when no optokinetic stimulation occurs.

Adult↗