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Alzheimer's disease (AD) has traditionally been considered solely a neurological condition. Therefore, numerous studies have been conducted to identify the existence of pathophysiological changes affecting the brain and the blood-brain barrier in individuals with AD. Such studies have provided invaluable insight into possible changes to the central nervous system exposure of drugs prescribed to individuals with AD. However, there is now increasing recognition that extra-neurological systems may also be affected in AD, such as the small intestine, liver, and kidneys. Examination of these peripheral pathophysiological changes is now a burgeoning area of scientific research, owing to the potential impact of these changes on the absorption, distribution, metabolism, and excretion (ADME) of drugs used for both AD and other concomitant conditions in this population. The purpose of this review is to identify and summarise available literature reporting alterations to key organs influencing the pharmacokinetics of drugs, with any changes to the small intestine, liver, kidney, and circulatory system on the ADME of drugs described. By assessing studies in both rodent models of AD and samples from humans with AD, this review highlights possible dosage adjustment requirements for both AD and non-AD drugs so as to ensure the achievement of optimum pharmacotherapy in individuals with AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The first known reported case of relapsing polychondritis in a Latin American man is presented. The 35-year-old man, demonstrating auricular chondritis, arthritis, nasal cartilage involvement, episcleritis and respiratory tract chondritis, was admitted to the hospital and treated with 60 mg of prednisone daily, prednisolone acetate 1% ophthalmic drops every waking hour and homatropine hydrobromide 5% ophthalmic drops twice daily. After discharge from the hospital, he received 30 to 60 mg of prednisone daily and prednisolone acetate 1% ophthalmic drops twic daily for about 18 months. A permanent trachestomy was placed, azathioprine, 150 mg daily, was given and prednisone dosage was tapered to 25 mg daily when the patient subsequently was hospitalized for colapsed airway and Cushing's syndrome. The classic symptoms, pathogenesis and treatment of the disease are reviewed. Systemic corticosteroids are the drugs of choice in relapsing polychondritis, with immunosuppressive drugs, azathioprine in particular, being used as adjuvants to lower steroid dosage requirements and to achieve greater control of symptoms in patients with the severe progressive disease. Treatment of the disease with dapsone alone is promising and may offer an alternative to high-dose steroids and immunosuppressive therapy.

The pharmacokinetic parameters of lidocaine are pertinent to the determination of both appropriate loading doses and constant infusion rates that achieve a therapeutic plasma concentration while avoiding toxicity. Because lidocaine is used primarily in older patients who may have concurrent diseases, the effects of disease states on lidocaine disposition are important when calculating lidocaine doses. Patients with congestive heart failure and hepatic disease have pronounced changes in lidocaine clearance. Patients placed on prolonged lidocaine infusions have a change in disposition half-life of the drug. Patients with renal disease do not have significant alterations in handling the parent compound but, because of the dependence of glycinexylidide elimination on renal function, may accumulate the metabolite and develop central nervous system toxicity. Even though there are differences in some of the pharmacokinetic variables for lidocaine in young and elderly patients, the clearance of the drug was not significantly different in the two patient groups. The effects of concurrently administered drugs on lidocaine pharmacokinetics remain to be more widely studied in patients.

Four normal male volunteers participated in a study designed to examine the disposition of gold given intramuscularly as gold sodium thiomalate. Blood samples were collected for 32 days following the administration of 10 mg of gold sodium thiomalate. Plasma gold concentrations were determined by atomic absorption spectrometry. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 25 days. Apparent total body clearance of gold was 7.0 +/- 0.6 ml kg-1 day-1 and the apparent volume of distribution was 0.26 +/- 0.051 kg-1. These pharmacokinetic data are in contrast to previous data from other investigators who have reported half-lives of approximately 5 days. Data from the current study provide a sound rationale for the currently used empiric dosing regimens.

Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup-plate technique with M. luteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration-time curve (AUC) two-fold and decreased the total body clearance significantly with decreases in both renal and non-renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non-renal clearances of nafcillin.

Indomethacin, an indole derivative nonsteroidal anti-inflammatory drug, has been available since the early 1960s in gelatin capsules. In 1982, a sustained release product, Indocin SR, was marketed. Awaiting marketing approval is a unique controlled release form of indomethacin, Indos. The disposition of indomethacin includes enterohepatic cycling and extensive metabolism to inactive metabolites. Enterohepatic cycling makes interpretation of bioavailability estimates of indomethacin dosage forms difficult. The relationship of indomethacin plasma concentration to therapeutic effects and side effects is inconclusive. It appears in vivo prostaglandin inhibition occurs at very low plasma concentrations that are achievable with all available dosage forms. Indocin SR is a sustained release capsule of indomethacin designed to deliver 25 mg of drug immediately and 50 mg gradually. Absolute bioavailability of the product is 80%. The plasma concentration-time curves do not show good sustained release characteristics; after four hours plasma concentrations resemble those seen with a single dose of regular capsule. The cost compared with Indocin is competitive. Indos is a zero-order release form of indomethacin. It is a unique drug delivery system that shows good controlled release characteristics. Bioavailability is 85%. Both Indocin SR and Indos are apparently therapeutically equivalent to indomethacin capsules. In elderly patients, Indos has been shown to be associated with fewer side effects than Indocin. Both Indocin SR and Indos have the advantage of once or twice daily dosing.

Furosemide (40 mg) was administered to 18 healthy adult males as an intravenous dose, an oral solution, and in tablet form. The pharmacokinetics of intravenous furosemide were studied, determining a total body clearance rate of 117.6 +/- 41.3 ml/min and a harmonic mean half-life of 78 min. The mean absolute bioavailability determined by ratio of areas under the plasma-time curves was 64 and 71% for the solution and tablet, respectively. The mean absolute bioavailability determined by the ratio of urinary cumulative excretion data was 61 and 66% for the solution and tablet, respectively. The absolute bioavailability of furosemide determined with plasma and urine data were not significantly different. Thus, urine data alone may be used to establish bioavailability of furosemide. Inspection of plasma-time curves revealed secondary maxima in several subjects, suggesting enterohepatic cycling.

Furosemide tablets, with markedly different dissolution characteristics, and solution were orally administered to 21 healthy adult males to determine the effect of in vitro dissolution rate on in vivo bioavailability profiles. Furosemide 40 mg was given as Tablet A (fast dissolution characteristics), Tablet B (slow dissolution characteristics), and an aqueous solution. Both batches of tablets had identical formulae and were produced by a common process. The dissolution rate of the slower Tablet B was probably retarded by extension of the wet granulation time. Blood was collected for 12 h postdose and urine for 24 h. Peak plasma furosemide concentrations after the solution were significantly greater than after the tablets; there was no significant difference between the tablets. The time to peak occurred significantly earlier with the solution, with no significant difference between the tablets. Relative bioavailabilities of Tablet A and B were 89 per cent and 101 per cent, respectively, as determined by AUC, and 79 per cent and 84 per cent, respectively, as determined by urine recovery. These differences are not statistically significant. These results indicate that dissolution rate profiles of furosemide tablets may not be predictive of in vivo bioavailability.

Data from a long-term, open-label diltiazem trial were analyzed to test the hypothesis that the magnitude of systolic blood pressure (SBP) response to diltiazem is dependent on pretreatment levels. The study design included a 2- to 4-week placebo period to establish stable qualifying pressures. Patients devoid of significant coexisting diseases with diastolic blood pressures (DBPs) greater than or equal to 95 mm Hg or SBPs greater than or equal to 160 mm Hg were titrated on sustained-release diltiazem (60-180 mg b.i.d.) over 2-6 weeks. Titration goals were greater than or equal to 10% drop in DBP or greater than or equal to 15% in SBP. Patients were followed up to 20 months. Based on pretreatment blood pressure, patients were divided into three subgroups: isolated systolic hypertension (ISH) (SBP/DBP; greater than or equal to 160/less than 95 mm Hg), isolated diastolic hypertension (IDH) (less than 160/greater than or equal to 95 mm Hg), and combined systolic and diastolic hypertension (CSDH) (greater than or equal to 160/ greater than or equal to 95 mm Hg). SBP changed significantly from baseline for all three groups. However, the percent reduction in SBP was significantly greater for patients with baseline SBP greater than or equal to 160 mm Hg when compared with patients with baseline SBP less than 160 mm Hg (-10.3 +/- 0.7% vs. -4.4 +/- 0.6%). In comparing the ISH and CSDH patient groups, the CSDH group required a larger diltiazem dose to achieve a SBP response similar to the ISH group. Diltiazem was well tolerated with only a 5% dropout due to adverse effects of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of pentoxifylline was studied in healthy male volunteers following single oral doses of 100, 200 and 400 mg of the drug in solution. Concentrations of the drug and three of its metabolites were determined in plasma. The major urinary metabolite was also determined for 24 hours after dosing. Pentoxifylline was rapidly and extensively absorbed at all doses. Peak plasma concentrations of pentoxifylline occurred between 0.29 and 0.41 hours after dosing. Its metabolites, a secondary alcohol and two homologous carboxylic acids showed tmax values from 0.72 to 1.15 hours. Cmax and AUC values increased in a dose-dependent manner for pentoxifylline and its metabolites over the three dose levels though strict dose proportionality could only be demonstrated for the principal carboxylic acid metabolite. The apparent plasma half-life of pentoxifylline varied between 0.39 and 0.84 hours for the various doses while the apparent half-lives of the metabolites were in the range of 0.96 to 1.61 hours. The major circulating metabolites, the secondary alcohol and carboxypropyl derivative, were at consistently higher plasma concentrations than the parent drug. Two major pathways account for the circulating metabolites of pentoxifylline though oxidation of the parent drug to a carboxylic acid accounts for the formation of the principal urinary elimination product. Because of the pharmacological activities of pentoxifylline, studies are proposed of the pharmacokinetic-pharmacodynamic correlations of pentoxifylline and its metabolites. The present pharmacokinetic results further support the use of a controlled-release dosage form of pentoxifylline for therapy.

A 49-year-old woman treated with cimetidine 300 mg tid for more than 18 months for Zollinger-Ellison syndrome experienced lethargy, dizziness, ataxia, and auditory and visual hallucinations after receiving triazolam 0.375 mg hs for sleep. Triazolam plasma concentrations were measured, and a triazolam elimination half-life was calculated to be approximately 8 hours (reported range 1.7-3 h). Cimetidine has been reported to decrease the apparent oral clearance of triazolam, resulting in increased triazolam plasma concentrations with the potential for exaggerated triazolam pharmacologic effects. Cimetidine may have been responsible for the unusually large elimination half-life in this patient. Until the mechanisms and clinical significance of this potential drug interaction are determined, clinicians should use the combination of triazolam and cimetidine with caution.

Two normal males participated in a study designed to examine the disposition of gold given intravenously and intramuscularly as gold sodium thiomalate. Blood samples were collected for 30 days, urine and feces for ten. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 12.5 days. Absolute bioavailability of IM gold sodium thiomalate appears to be variable with one subject having complete absorption and the other absorbing 64% of the administered IM dose. The major route of elimination of an IV dose of gold sodium thiomalate is urinary excretion, with a mean of 35% of the dose found in the urine in ten days. Fecal elimination accounts for an additional 9.4% of the IV dose excreted in ten days, probably as a result of biliary secretion.

Furosemide solution was orally administered to 21 healthy adult males to determine dose proportionality over the dose range used and the reproducibility of disposition following a repeated dose. Furosemide solution was given in doses of 20, 40, and 80 mg, with the 40 mg dose repeated once. Blood was collected for 12 hours post-dose and urine for 24 hours. The maximum plasma concentrations resulting from 20, 40, and 80 mg doses were significantly different (p less than 0.05). Dose normalized maximum concentrations for the 20 and 80 mg doses were significantly different (p less than 0.05). Mean time to Cpmax was 50 minutes, with no differences observed among doses. Plasma AUCs were significantly different (p less than 0.05) for 20, 40, and 80 mg. Dose normalized AUCs were not significantly different. Mean amounts of furosemide in urine (Xu) were 9.62, 16.7, and 32.0 mg for the 20, 40, and 80 mg doses, respectively. These amounts were significantly different (p less than 0.05); dose normalized amounts were not significantly different. Renal clearances of furosemide following the three doses were not significantly different. Regressions of Cpmax, AUC and Xu on dose were significant. There were no significant differences in Cpmax, tmax, AUC or Xu for 40 mg given on two separate days. Renal clearance of furosemide was statistically different for 40 mg given on two separate days, but the difference was not clinically significant. The pharmacokinetics of furosemide are linear over the dosage range studied. Furosemide 40 mg given on two separate days results in similar disposition parameters.