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Biomedical subjects

A J Jackson

Publications and source records attributed to A J Jackson.

At least 55 records · Page 3Linked to original sources
PubMed1991

Easy and practical utilization of CONSAM for simulation, analysis, and optimization of complex dosing regimens.

Complex dosing regimens simulated in the literature using a universal dosing regimen were calculated with a general dosing program developed using the program CONSAM. The program provides a rapid method of calculating nonuniform dosing regimens for up to n = 3 compartments for any linear model. Subject data can also be curve fitted with the program to obtain individual subject estimates to allow for dosage optimization, which is important in a clinical setting. Examples are presented to show the use of the program in optimizing a theophylline regimen, as well as estimation of a new parameter, Cuneq(T), which is defined as the average non-steady-state drug concentration at time t for a drug with an irregular dosing interval.

Computer Simulation↗
PubMed1991

Suitability of various noninfinity area under the plasma concentration-time curve (AUC) estimates for use in bioequivalence determinations: relationship to AUC from zero to time infinity (AUC0-INF).

The influence of random error and elimination rate on estimates of the area under the curve from zero to time infinity (AUCO-INF) was determined in a simulation study using noninfinity measured AUC values (i.e. AUCTM, area to a measured common sampling time, and AUCO-LAST, area to the last measured sampling time). Further, the extent of absorption of generic danazol, baclofen, and oxazepam was determined using measured methods of estimating area under the curve in bioequivalence studies. The noninfinity AUC estimates and their 90% confidence intervals for the difference in product means were compared for each individual drug. Products chosen fulfilled one of the following three criteria: (1) a high "apparent intrasubject variability" and a half-life greater than 8 hr (danazol); (2) a low apparent intrasubject variability and a half-life less than 4 hr (baclofen); and (3) products exhibiting a low apparent intrasubject variability and a half-life greater than 8 hr (oxazepam). For the simulated data, AUCTM performed best when subjects had similar half-lives (i.e., low variability), which results in AUCTM = AUCO-LAST. On the other hand, AUCO-LAST worked best with a high fractional standard deviation (fsd) and a short elimination half-life (i.e., less than 4 hr). The noninfinity 90% confidence intervals for danazol and oxazepam were inconsistent with those observed at AUCO-INF.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

The role of metabolites in bioequivalency assessment. I. Linear pharmacokinetics without first-pass effect.

The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using Cmax of parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of Cmax values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for Cmax of the metabolite and, in turn, a tighter confidence interval for Cmax of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for Cmax of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.

Acetohexamide↗
PubMed1991

The provision of ophthalmic services for a rehabilitation day care centre population with multiple physical handicaps.

The provision of the wide variety of support services necessary for patients with multiple handicaps is often poorly coordinated. In this study a group of 108 adults, aged from 19 to 90 years, who suffered from multiple physical handicaps and attended a rehabilitation day care centre, had their visual functions and requirements assessed by a multidisciplinary team. The programme consisted of five stages. Each patient was initially screened and subsequently referred for more detailed optometric, ophthalmological, low vision or rehabilitation assessments, where appropriate. Results indicated that many of the patients had not been receiving regular ocular assessments and would benefit from the provision of an optical appliance or ophthalmological treatment. The survey provided staff at the rehabilitation centre with information on the visual status of individual patients and enhanced general eye-care awareness.

Adult↗
PubMed1990

Naloxone-induced ACTH release in man is inhibited by clonidine.

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the alpha 2-adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone-induced ACTH secretion in normal human volunteers. 2. There was a significant blunting of the mean peak level of ACTH and the mean peak change of ACTH from basal as well as the area under the ACTH-time curve when clonidine was given prior to naloxone. 3. We conclude that clonidine, by blocking central noradrenergic pathways, which stimulate corticotropin-releasing hormone secretion, inhibits naloxone-induced ACTH secretion. This suggests that naloxone causes ACTH release through these same central noradrenergic pathways.

Administration, Oral↗
PubMed1989

Influence of the routes of continuous intrahepatic infusion of 5-fluorouracil on its pharmacokinetics.

Continuous infusion chemotherapy via hepatic artery using newly available mechanical devices is frequently used to treat hepatic metastases to achieve a high concentration of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure. We compared four routes of intrahepatic administration to find out the best one in the canine model. To ascertain this data, 5-FUra (30 mg/kg) was given as a continuous infusion over a 3 hr period into either a systemic vein (femoral), portal vein, hepatic artery, or hepatic artery distal to its ligation after hepatic dearterialization. A total of eight dogs were studied. During 5-FUra infusion, concomitant blood samples were taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, 60, 120, and 180 min. 5-FUra levels were determined in plasma by high-performance liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data described by a multicompartmental model, including the measured flows, had separate hepatic arterial and portal compartments with elimination from each described by linear kinetics. Mean area under the curve values in microgram/ml X min and the ratios of the systemic/hepatic vein areas following 5-FUra infusion via systemic, portal vein, hepatic artery, or hepatic artery after dearterialization routes were: 975/539 (R = 1.80), 939/748 (R = 1.35), 211/454 (R = 0.46), and 562/1,424 (R = 0.39). The results indicated that the administration of 5-FUra via the hepatic arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest systemic/hepatic vein exposure ratio, followed by intra-arterial route, while systemic and portal vein routes were not nearly as advantageous as the intra-arterial routes.

Animals↗
PubMed1989

Nifedipine blocks ACTH and cortisol release in man.

1. The present study investigated the effect of prior administration of nifedipine on AVP-induced ACTH release in seven normal volunteers. Three protocols were used: 20 mg oral nifedipine; 0.14 pressor units intramuscular (i.m.) per kg bodyweight aqueous AVP; oral nifedipine plus i.m. AVP 90 min later. Plasma ACTH and cortisol were measured at intervals for 2.5 h during each test. 2. The mean peak plasma ACTH and cortisol levels and the mean peak changes from basal in these levels were significantly lower in the nifedipine/AVP test than in the AVP alone test. The integrated area under the cortisol time curve was significantly lower for the nifedipine/AVP test than that for the AVP test alone. Nifedipine alone caused no changes in ACTH or cortisol. 3. Acute administration of oral nifedipine caused an inhibition of AVP-stimulated ACTH and cortisol release in normal humans. This effect may be due to blockade of plasma membrane calcium channels normally activated during AVP stimulation of pituitary corticotrophs.

Adrenocorticotropic Hormone↗
PubMed1989

Potentiation of fenfluramine-induced ACTH release in man by naloxone.

1. This study set out to compare the effect of the combination of fenfluramine (Fen) and naloxone (Nal) on ACTH and cortisol release with each of these agents alone in six normal volunteers. Three protocols were used: 1.5 mg/kg bodyweight oral Fen; 125 micrograms/kg bodyweight i.v. Nal; oral Fen plus i.v. Nal 135 min later. Plasma ACTH and cortisol were measured at intervals of 285 min over each test. 2. The mean peak levels and mean peak changes from basal in plasma ACTH and cortisol were significantly greater in the combination test (Fen/Nal) than in either the Fen alone or the Nal alone tests. Fen and Nal given together cause a synergistic release of ACTH and cortisol as determined by the areas under the ACTH-time and cortisol-time curves for Fen/Nal compared to the sums of Fen alone plus Nal alone curves for ACTH and cortisol. 3. We conclude that Fen and Nal acting synergistically work through different and potentiating mechanisms at the hypothalamic, central nervous system and/or pituitary levels to cause ACTH release.

Adrenocorticotropic Hormone↗
PubMed1988

Inhibition of serotonin-induced ACTH release in man by clonidine.

1. Clonidine, an alpha 2-adrenergic agonist, is thought to inhibit noradrenergic neuronal activity (NNA) in the central nervous system (CNS) by a presynaptic alpha 2-receptor mechanism. Central NNA is thought to be the primary monoaminergic stimulus to pituitary ACTH release. Fenfluramine, a serotonin releasing agent and uptake inhibitor, causes ACTH release in normal man. 2. The present study investigated the effect of clonidine on fenfluramine-induced ACTH release in six normal volunteers. Four protocols were used: 1.5 mg/kg body weight oral fenfluramine; 4.3 micrograms/kg body weight oral clonidine; oral clonidine + oral fenfluramine 1 h later; placebo clonidine. Plasma ACTH and cortisol were measured at intervals for 5 h after clonidine and for 4 h after fenfluramine. 3. The mean plasma ACTH and cortisol levels and the mean maximal changes in these levels were significantly lower during the clonidine + fenfluramine test than during fenfluramine alone. Plasma ACTH and cortisol levels were not lowered significantly more by clonidine than by placebo. 4. In conclusion, clonidine blocked the ACTH-releasing activity of fenfluramine in normal humans. This inhibition of active ACTH release may result from clonidine blockade of fenfluramine-induced activation of central NNA. Clonidine alone was no more effective than placebo in lowering plasma ACTH and cortisol.

Adolescent↗
PubMed1987

Application of moment analysis in assessing rates of absorption for bioequivalency studies.

Moment analysis was utilized in the evaluation of equivalency between test and reference formulations with respect to the rate of absorption for four drugs having different pharmacokinetic characteristics. A confidence interval technique was applied to compare the three relevant absorption parameters, that is, peak plasma concentration (Cmax), time to peak plasma concentration (tmax), and mean absorption time (MAT). Equivalence in the absorption rate of drugs was found to be best evaluated by the combined use of MAT, tmax, and Cmax. Use of these parameters for assessing equivalency requires careful interpretation of the results of statistical analysis as well as appropriate consideration of efficacy and safety issues for individual drugs. In addition, the statistical moment method proves to be useful in the assessment of bioequivalency, particularly for drugs with multiple absorption maxima.

Acetaminophen↗
PubMed1987

Adrenaline infusion and adrenocorticotrophin (ACTH) and cortisol release in normotensive and hypertensive man.

1. Adrenaline causes ACTH release from cultured rat pituitary corticotrophs (Vale et al. 1983) and there is evidence that it causes ACTH release in rats in vivo (Plotsky et al. 1985). 2. The present study examined the effects of intravenous adrenaline infusion with and without simultaneous administration of the known ACTH secretagogue, arginine vasopressin, in normotensive and mild essential hypertensive men on their plasma ACTH and cortisol levels. 3. Low dose adrenaline infusion (0.013 microgram/kg per min) does not cause ACTH or cortisol release, but appears to blunt the ACTH and cortisol rise caused by arginine vasopressin (0.14 pressor units/kg, i.m.).

Adrenocorticotropic Hormone↗
PubMed1987

Cefoxitin interferes with the "Clini-Skreen" column method for urinary 17-hydroxycorticosteroids.

Cefoxitin interferes with determination of urinary 17-hydroxycorticosteroids. The apparent concentration of hormone is increased from three- to 10-fold in samples from patients receiving cefoxitin when the Amberlite XAD-2 "Clini-Skreen" column is used. To determine the mechanism of interference, we reacted aqueous solutions of cefoxitin, cortisol, cortisone, and 11-deoxycortisol with phenylhydrazine; recorded the adsorption spectra; and determined the molar absorptivities and the equilibrium and rate constants. Also, we recorded the absorption spectra of phenylhydrazine with eight other cepha antibiotics and benzylpenicillin. Cortisol, cortisone, 11-deoxycortisol, and cefoxitin react with phenylhydrazine and absorb light with superimposable spectra and absorption maxima of 410 nm. The other antibiotics react with phenylhydrazine but absorbance maxima of the products vary, none being at 410 nm. Cortisol, cortisone, and 11-deoxycortisol react with phenylhydrazine 35-fold faster, have equilibrium constants ninefold greater, and have molar absorptivities 1.6 times that of cefoxitin. Thus, cefoxitin interferes with determination of urinary 17-hydroxycorticosteroids by forming a chromophore with the same absorbance maximum and with a molar absorptivity similar to cortisol, but much more slowly.

17-Hydroxycorticosteroids↗
PubMed1986

Toxicity and complications of vascular isolation and hyperthermic perfusion with imidazole carboxamide (DTIC) in melanoma.

The authors have used imidazole carboxamide (DTIC) in vascular isolation and hyperthermic perfusion for melanoma. The regional and systemic toxicity and complications of this procedure were studied in 40 cases with Stage III (15) and Stage I (25) melanoma. Technetium 99m-labelled serum albumin crossover and pharmacokinetic studies were done simultaneously to see if these correlate with toxicity. Local toxicity on muscles, nerves, skin, and arteries was conspicuously absent despite using dosages of 2 g/m2 (40-45 mg/kg) for the lower extremity and 1.2 g/m2 (24-28 mg/kg) for the upper extremity. Skin and core temperature were raised to 39 degrees C to 40 degrees C. Deep vein thrombosis was noted in three patients. No death or gangrene of the extremities occurred. Local infection was noted in only one patient. Fourteen patients (35%) manifested bone marrow toxicity (leukocyte count of 4000/mm3 or platelets of 100,000/mm3) in the second or third week after perfusion. Severe hematologic toxicity was seen in two instances. Dosages of DTIC greater than 40 mg/kg were associated with toxicity in 65% of the patients. No bleeding complications occurred in seven patients with thrombocytopenia. Measurement of crossover and recovery of radionuclide were not reliable indicators of subsequent systemic toxicity. Perfusion fluid balance data also were of no predictive value. Forty-seven percent of the administered DTIC was recovered in washout fluid. Of this, less than 2% was converted to its metabolites, that is aminoimidazole carboxamide and 2-azahypoxanthine. Thirty-five of 40 patients experienced mild nausea and vomiting. Transient and mild hepatotoxicity was noted in seven patients. It appears that DTIC hyperthermic isolation perfusion is a safe procedure, however, the total dosage should be below 40 mg/kg to avoid hematologic toxicity.

Adult↗
PubMed1986

Long term observations on an anterior chamber Ridley intraocular lens.

In 1965 the patient, aged 6, sustained a perforating eye injury which was repaired and a traumatic cataract was aspirated within five weeks. Five years later a Ridley Mk 2 A/C intraocular lens was inserted. Several episodes of blunt trauma occurred over a three year period following this procedure. This paper reports the clinical, corneal pachometric and specular microscopic findings of both traumatized and normal fellow eyes 18 years after the initial incident. The corneal endothelial mosaic of the traumatized right eye was very irregular in the vicinity of the initial site of perforation. These marked variations in cell size and shape were less apparent at peripheral corneal areas. The estimated cell loss to the traumatized eye was in the region of 74% although in spite of this corneal function was maintained. The effects of trauma on the corneal endothelium are discussed and a brief review of the literature presented.

Anterior Chamber↗
PubMed1985

Simultaneous determination of dacarbazine, its photolytic degradation product, 2-azahypoxanthine, and the metabolite 5-aminoimidazole-4-carboxamide in plasma and urine by high-pressure liquid chromatography.

A high-pressure liquid chromatographic method has been developed that allows for the simultaneous analysis of dacarbazine (DTIC), 5-aminoimidazole-4-carboxamide (AIC), and 2-azahypoxanthine (2-AZA) in plasma or urine. Plasma samples were prepared by ultrafiltration, whereas urine samples were filtered and diluted for analysis. Chromatography was done with a C18 mu Bondapak column along with gradient elution of the drugs. The mobile phase consisted of 100% 0.5 M sodium acetate (pH 7.0) and 25% acetonitrile in 0.05 M sodium acetate (pH 5.5) with detection at 280 nm. Linearity was observed up to 500 micrograms/ml for DTIC and up to 53 micrograms/ml for AIC and 2-AZA. The assay methodology was reproducible, with a lower limit of detection of 5.0, 0.5, and 0.5 micrograms/ml for DTIC, AIC, and 2-AZA, respectively. Interday and intraday coefficients of variation ranged between 4 to 14% and 2 to 16%, respectively. The analytical method was applied to the analysis of plasma and urine samples resulting from the isolation perfusion chemotherapy of an extremity with 57 mg of DTIC per kg in a patient with melanoma.

Aminoimidazole Carboxamide↗
PubMed1985

Unresectable hepatic metastases from carcinoma of the colon and rectum.

To alter the dismal prognosis of multiple unresectable metastases to the liver from carcinoma of the colon and rectum, 30 patients underwent hepatic dearterialization (ligation of the hepatic artery, transection of hepatic ligaments and cholecystectomy) and distal hepatic artery cannulation with prolonged infusion chemotherapy by a portable infusion pump followed by systemic intravenous chemotherapy. Involvement of the liver by carcinoma was less than 50 per cent in 16 and more than 50 per cent in 14 patients. The results of follow-up examinations, LFT, CEA and CT scan studies showed more than 50 per cent regression of the tumor and a decrease in alkaline phosphatase values and CEA in 29 patients (97 per cent); six had complete regression of tumor. The duration of response ranged from five to 39 months with the median of 17 or more months. The results of sequential LFT showed immediate increase in liver enzymes with return to normal in seven to 14 days. The mean CEA value decreased by 69 per cent within the first week and further decreased by 88 per cent in two months at the end of infusion chemotherapy. The over-all and adjusted survival rates from diagnosis were 79 and 91 per cent at 12 months; 56 and 81 per cent at 18 months, and 40 and 65 per cent at 24 months. The over-all and adjusted median survival rate after the treatment was 17 and 23 months, respectively. Of the 14 patients who failed this program, 11 had recurrences at sites other than the liver, with hepatic disease in remission in the majority. Of the 17 patients who died, six died of causes unrelated to the recurrence of disease. Thus, hepatic dearterialization and infusion regional chemotherapy can "effectively" control the hepatic disease and increase over-all survival time from three to six months to 23 months. However, recurrences of extrahepatic carcinoma and other causes are responsible for death and the over-all guarded prognosis.

Adult↗