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Biomedical subjects

P L Williams

Publications and source records attributed to P L Williams.

At least 19 recordsLinked to original sources
PubMed1992

Quantitative prediction of transdermal iontophoretic delivery of arbutamine in humans with the in vitro isolated perfused porcine skin flap.

The use of the isolated perfused porcine skin flap (IPPSF), an alternative in vitro animal model, to predict the profile of the concentration of arbutamine in plasma samples from humans after transdermal iontophoretic administration of this novel catecholamine is described. The strategy involved administering the drug in the IPPSF (n = 8) and assaying concentrations of drug in the venous efflux versus time (IPPSF venous efflux profile). Intravenous infusion (n = 7) and transdermal studies (n = 32) were also conducted in humans. The IPPSF profile was then used as an input into an intravenous pharmacokinetic model obtained from the human experiments to predict the profile of concentration of drug in plasma versus time (plasma concentration-time profile) seen after iontophoretic administration. The IPPSF profiles were denormalized according to the parameters used in the human studies (i.e., multiplied by in vivo concentration, electrode area, current, and dosing time). For two different sets of iontophoretic dosing conditions, the concentration-time profiles that were predicted on the basis of the IPPSF study were compared with those seen after delivery to humans.

Administration, Cutaneous↗
PubMed1992

Vasculitic and encephalitic complications associated with Coccidioides immitis infection of the central nervous system in humans: report of 10 cases and review.

Six cases of apparent and four cases of histopathologically confirmed vasculitis of the central nervous system (CNS), including one case of histopathologically documented vasculitis with encephalitis associated with coccidioidal meningitis (CM), are presented. Vasculitic complications included changes in mental status as well as stroke-like findings of aphasia, hemianopsia, and hemiparesis. Seven patients died. Vasculitic complications were unanticipated and often abrupt in onset, and delayed therapeutic intervention was characteristic. The diagnosis of vasculitis/encephalitis due to Coccidioides immitis infection must be based on clinical judgment, since serum antibody titers, cerebrospinal fluid findings, and initial radiological studies are not always helpful. Institution of both intravenous and intracisternal administration of amphotericin B and possibly concomitant intravenous administration of dexamethasone may be warranted in situations in which the association of C. immitis with CNS vasculitis or encephalitis appears likely before serologic or cultural confirmation of C. immitis infection involving the CNS is available.

Adult↗
PubMed1992

Psychological effects of sodium valproate and carbamazepine in epilepsy.

Information from standardised tests of intelligence, school attainments, attention, memory and visuomotor function, together with parent and teacher questionnaire information about various aspects of behaviour, was obtained for 63 schoolchildren with newly diagnosed epilepsy before treatment with sodium valproate or carbamazepine, and again at intervals for a total period of 12 months. The same information was collected on 47 matched controls. The children with epilepsy represented those under non-specialised paediatric care. The result showed that both drugs were effective in most cases at modest dosage without causing notable psychological effects 12 months into treatment. Modest and temporary adverse cognitive effects seen earlier in treatment could have been the result of uncontrolled seizure discharge. Improved function was the same in children with epilepsy and controls. Some psychological abnormalities in the children with epilepsy were evident before treatment suggesting early unwanted effects of the epileptic process itself.

Carbamazepine↗
PubMed1991

Effects of vasoactive drugs on transdermal lidocaine iontophoresis.

The effect of co-administration of vasoactive drugs on the transdermal iontophoretic delivery of lidocaine.HCI was studied in in vitro cells, in the isolated perfused porcine skin flap (IPPSF), and in vivo in pigs. Iontophoresis of lidocaine in vitro across human and porcine skin were similar, supporting the use of porcine skin as an appropriate animal model. Co-iontophoresis of the vasodilator tolazoline marginally decreased lidocaine flux in vitro, but significantly increased it in the IPPSF and in vivo. In contrast, norepinephrine decreased lidocaine flux in the IPPSF. Vasomodulation also changed the shape of the venous efflux profile in the IPPSF as evidenced by changes in fractional absorption index, as well as the AUC. These studies demonstrate that co-iontophoresis of vasoactive compounds may significantly alter the transdermal delivery of lidocaine and that use of vitro animal model systems which possess a functional microcirculation are essential to study this process if reliable extrapolation to the in vivo setting is desired.

Administration, Cutaneous↗
PubMed1991

Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs.

Cisplatin (90 mg/m2) was administered in a 5-minute bolus IV infusion to dogs at 8 AM (n = 6) or 4 PM (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 PM (PM group), compared with those treated at 8 AM (AM group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in BUN, serum creatinine concentration, urine gamma-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and BUN were significantly increased in the AM group, compared with the PM group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.

Animals↗
PubMed1990

A physiologically relevant pharmacokinetic model of xenobiotic percutaneous absorption utilizing the isolated perfused porcine skin flap.

A physiologic pharmacokinetic model describing percutaneous absorption of topically applied compounds in the isolated perfused porcine skin flap (IPPSF) is presented. As an extension of a previously reported hybrid physiologically relevant compartmental model of uptake of intra-arterially administered drug in the IPPSF, this percutaneous model should allow experimental results obtained from an in vitro preparation to serve as quantitative input to an in vivo pharmacokinetic system. Model parameters estimated from 8-10-h IPPSF experiments were able to predict 6-day in vivo radiolabel absorptions in pigs for topically applied benzoic acid, caffeine, malathion, parathion, DFP, testosterone, and progesterone. These results compare favorably with those obtained previously using a classical compartmental modeling approach.

Animals↗
PubMed1989

Serum lipolytic activity in Reye's syndrome.

High levels of the serum free fatty acids (FFA) are found in Reye's syndrome (RS). While this is attributed to enhanced adipose tissue lipolysis, the possibility that intravascular lipolysis could augment this process was investigated by measuring lipase activity in sera from RS and other subjects. Ordinarily, lipolytic activity is not detectable in serum from unheparinized subjects. Significant lipolytic activities ranging from 1-3 mumol/ml serum per hour were detected in sera from 5 of the 7 RS patients studied. Similar activities were also found in sera from two other subjects one of whom was a long-term survivor of RS and the other who had recurrent bouts of biliary obstruction and encephalopathy. Lipase activity was negligible in the serum from 2 other RS patients, 4 other long-term survivors of RS, 2 siblings, one RS parent and in 20 disease controls including patients with influenza, diabetic ketoacidosis and cerebral edema, meningitis and febrile infections with diarrhea and vomiting. None of these individuals had received heparin. An inverse relationship was found between LPL and hepatic lipase (HL) activities. Glucose levels tended to correlate directly with LPL and inversely with HL activity. The basis for the presence of LPL activity in RS sera is not known but the presence of serum lipase activity in unheparinized patients supports the notion that the TG in the circulating lipoprotein particles probably also serve as another source of FFA in the sera of RS patients.

Child↗
PubMed1989

Definition of a physiologic pharmacokinetic model of cutaneous drug distribution using the isolated perfused porcine skin flap.

A physiologic pharmacokinetic model describing drug disposition in the isolated perfused porcine skin flap (IPPSF) is derived. The IPPSF is well suited for experimental studies of dynamic drug distribution into skin because arterial and venous drug fluxes can be continuously monitored. The system parameters of the model are uniquely identifiable and describe the cutaneous efflux profile as a function of arterial input flux and tissue partitioning or extraction. This model allows experimental results obtained from an in vitro preparation to serve as a quantitative input to an in vivo, whole animal pharmacokinetic system. Experimental infusion applications of the cancer chemotherapeutic agents cisplatin and carboplatin and the antimicrobials tetracycline and doxycycline are reported herein.

Animals↗
PubMed1989

The isolated perfused porcine skin flap. III. Percutaneous absorption pharmacokinetics of organophosphates, steroids, benzoic acid, and caffeine.

The isolated perfused porcine skin flap (IPPSF) has been developed as an alternative in vitro tool for examining the pharmacokinetics and mechanisms of percutaneous absorption. In this study, dosing solutions of seven 14C-radiolabeled compounds representing three chemical classes--organic acid/base [benzoic acid (B), caffeine (C)], organophosphate (OP) pesticides (diisopropylfluorophosphidate, malathion, parathion), and steroid hormones (progesterone, testosterone)--were prepared in ethanol and applied topically at a surface concentration of 40 micrograms cm-2 to the IPPSF. A three-compartment pharmacokinetic model used to stimulate mass transfer from the surface (C1), diffusion through epidermis and dermis (C2), and transfer into the capillary perfusate (C3), was developed based on flux through the IPPSF from 0 to 8 hr. This basic model accurately stimulated measured IPPSF fluxes for five of seven compounds, including the OPs and steroids. The model was modified to simulate the shunting of drug to fast and slow release pathways, which occurred for B 3-4 hr postapplication, and to account for flow-dependent flux increases seen for C at 6 hr postapplication. The latter may be due to a direct pharmacologic effect, since C is a known vasodilator. Extrapolated (to 6 days) areas under the curve from the model simulations were compared with in vivo percutaneous absorption estimates, obtained from 6-day excretion studies in pigs. The in vivo-in vitro correlation, based on simple linear regression across compounds, was excellent (R2 = 0.88, R = 0.94, p less than 0.002). These results suggest that xenobiotic penetration in the 8-hr IPPSF experiments is highly predictive of in vivo absorption totals (6-day studies). In addition, since pig and human skin are similar physiologically and pharmacologically, the IPPSF may eventually have applications in formulating human dermal risk assessment models.

Animals↗
PubMed1989

Estimation of physiological volumes in the isolated perfused porcine skin flap.

A requirement for pharmacokinetic modeling of isolated perfused organ systems used for in vitro to in vivo extrapolations is a measure of the organ's physiological spaces. Two methods were employed to estimate intravascular and extracellular spaces in four isolated perfused porcine skin flaps (IPPSF) from 2 pigs. One of these methods used regression techniques based on a one-compartment model, and was found to be a good estimator of intravascular volume only. The other method was a non-parametric numerical integration technique, and was found to give reasonable estimates for both intravascular and extracellular volumes. The latter method's estimate for extracellular space was 0.20 +/- 0.03 mL/g, and the estimated vascular space by both methods was 0.08 +/- 0.01 mL/g.

Animals↗
PubMed1988

Treatment of mycoses with itraconazole.

The efficacy of itraconazole, a new oral triazole, was evaluated at doses of 50-400 mg/day in 64 courses: 39 with coccidioidomycosis, and 25 with other mycoses. Among patients with coccidioidomycosis, 21 had pulmonary disease; 10, bone and joint; 8, lymphatic; 6, skin and soft tissue; 3, meningeal; and 1, urogenital. After a mean of 7.1 months of treatment, 17 of 27 evaluable courses (63%) have shown a full response; 8 (30%), a partial response; and 2 (7%), no response. Response to treatment was higher in patients with a shorter duration of illness and in patients with no previous treatment. After a mean of 12 months of treatment, two of five responders off therapy have relapsed. In patients with other mycoses, diagnoses include aspergillosis in six patients; histoplasmosis and tinea in three each; alternariosis, candidiasis, cryptococcosis, blastomycosis, and chromomycosis in two each; and pseudallescheriosis in one. After a mean of 9.4 months of treatment, 14 of 23 evaluable patients (61%) have shown a full response; 2 (8%), a partial response; and 7 (30%), no response. All patients with histoplasmosis and blastomycosis have responded to therapy. There are no relapses among five evaluable responders after a mean of 9.2 months off therapy. In 512 patient months of therapy, toxicity has been minimal. Mean serum levels in patients receiving 200 mg twice daily range from 3.9 to 5.9 micrograms/ml for 8 hr after dosing, with a peak at 7 hr and wide interpatient variability. Itraconazole is well tolerated and has continued to demonstrate efficacy in the treatment of a variety of systemic and superficial mycoses.

Adult↗
PubMed1988

Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis.

The pharmacokinetics of fluconazole, a new oral azole, were evaluated in cerebrospinal fluid and sera of eight patients with coccidioidal meningitis. At a dose of 50 mg/day, peak concentrations of 2.5 to 3.5 and 2.0 to 2.3 micrograms/ml occurred at 2 to 6 and 4 to 8 h in serum and cerebrospinal fluid, respectively. At 100 mg/day, peak concentrations of 4.5 to 8.0 and 3.4 to 6.2 micrograms/ml occurred at 2 to 4 and 4 to 12 h, respectively. The mean ratios of the concentration in cerebrospinal fluid to that in serum were 73.8% at 50 mg/day and 88.7% at 100 mg/day. Results suggested that there was a prolonged half-life in both cerebrospinal fluid and serum and that it was slightly longer in the former. Minimal toxicity was noted in 34 patient months of therapy (12 months on 50 mg daily; 22 months on 100 mg daily). After a mean of 4.5 months of therapy, five patients responded to therapy and three were unevaluable. The penetration of fluconazole into cerebrospinal fluid was substantial, toxicity was minimal, and early clinical experience was encouraging. Fluconazole holds promise as the sole or adjunctive therapy for fungal meningitis.

Adult↗
PubMed1988

Using the nematode Caenorhabditis elegans to predict mammalian acute lethality to metallic salts.

The acute lethality of the salts of eight metals--HgCl2, BeSO4.4H2O, Al(NO3)3.9H2O, CuCl2.2H2O, ZnCl2, Pb(NO3)2, CdCl2, and Sr(NO3)2--was determined using a type of free-living nematode, Caenorhabditis elegans. The LC50 values were compared to the published mammalian oral LD50 values for salts of the same metals. Within this set of chemicals, C. elegans was found to be a predictor of mammalian acute lethality, generating LC50 values parallel to the rat and mouse LD50 values. The total expenses for this testing are about 10% of the cost for mammalian acute lethality testing. The method is considered to have great promise, but further study is needed.

Animals↗
PubMed1987

Imaging study of the painful heel syndrome.

A total of 45 patients with the painful heel syndrome without evidence of an associated inflammatory arthritis, seven of whom had pain in both heels, were studied using technetium-99 isotope bone scans and lateral and 45 degrees medial oblique radiographs of both feet. Of the 52 painful heels 31 (59.6%) showed increased uptake of tracer at the calcaneum. Patients with scans showing increased uptake tended to have more severe heel pain and responded more frequently to a local hydrocortisone injection. On plain x-ray, 39 of 52 painful heels (75%) and 24 of the 38 opposite nonpainful heels (63%) showed plantar spurs, compared with five of 63 (7.9%) heels in 59 age- and sex-matched controls. No evidence of stress fractures was seen.

Adult↗