Irving H. Gomolin

Older Is Colder: Temperature Range and Variation in Older People

Objectives: To ascertain body temperatures in older people.

Efficacy and safety of ciprofloxacin oral suspension versus trimethoprim-sulfamethoxazole oral suspension for treatment of older women with acute urinary tract infection.

OBJECTIVES: To compare the efficacy and safety of ciprofloxacin (CIP) oral suspension to trimethoprim/sulfamethoxazole (TMP/SMX) oral suspension among older women with acute urinary tract infections (UTIs).

Once-daily memantine: pharmacokinetic and clinical considerations.

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Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+.

Donepezil Dosing Strategies: Pharmacokinetic Considerations

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimers disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations.

Withdrawal of Antihypertensive Medications

Background: Pharmacologic treatment of hypertension reduces risks of stroke, congestive heart failure, renal failure, and mortality, but whether medications, once begun, need to be continued for life is uncertain. Methods: Several search strategies on MEDLINE using key words “medication,” “withdrawal,” “discontinuance,” and “therapy” in several combinations, nested within “hypertension,” were not productive. Accordingly, articles known to the authors and citations within them were reviewed. A survey of a random sample of members of the New York Academy of Family Practice was conducted to ascertain current practice of practicing physicians. Results: Eighteen studies of antihypertensive medication withdrawal were located and all were reviewed. In 12 trials average success rates of 40.3 percent after 1 year of follow-up and 27.7 percent after 2 years were achieved. In six studies limited to elderly patients, an average success rate of 26.2 percent was obtained for periods of 2 or more years. The trials, however, were heterogeneous in design, patient selection criteria, and follow-up. The survey of family physicians indicated that 79.1 percent attempt withdrawal of antihypertensive medications in hypertensive patients whose blood pressure is controlled and who are without symptoms from medication. Conclusions: We conclude that successful withdrawal of antihypertensive medications can have substantial benefits with few or no adverse consequences and might be successful in about one third of patients. Additional research is required to substantiate rates of successful medication withdrawal, to define the best method of withdrawing medications, and to delineate characteristics of patients in whom withdrawal is most likely to succeed.

Cholinesterase Inhibitors: Applying Pharmacokinetics to Clinical Decision Making

BACKGROUND Cholinesterase inhibitors are indicated for the treatment of Alzheimer-type dementia. There are few direct comparative studies of adverse effects or studies to suggest clinical superiority of one inhibitor over the others. OBJECTIVE The objective of this study was to relate pharmacokinetic differences among the agents to potential clinical considerations. METHODS Population pharmacokinetics were obtained from US Food and Drug Administration-approved label information and published literature. Plasma concentration-time profiles were derived from these parameters using noncompartmental pharmacokinetic modeling. RESULTS Plasma concentration profiles differed significantly among different agents and between different formulations of the same agent. CONCLUSIONS The initial choice among the various cholinesterase inhibitors requires consideration to adherence and cost. Consideration to differences in pharmacokinetics among these drugs provides a better understanding for the clinical practice of dose titration, identification and management of drug-related side effects, and lapses in therapy. Pharmacokinetic considerations among the various agents and formulations provide the clinician with options to enhance therapy when these agents are chosen for treatment of patients with Alzheimer-type dementia.

More on the Toxicity of Iodinated Glycerol

To the Editor:-In the March 1988 issue of the lournal, Wolf-Klein et all presented data susgesting that Alzheimer patients are healthier than other elderly patients. I would w e to raise a number of points in criticism. Although these findings have been suggested by studies of the prevalence of specific diseases in Alzheimer patients,I question whether the results of this study caq be generalized beyond the population studied. Patients who receive ,their care at centers like the Jewish Institute for Geriatric Care may not be representative of the elderly community at large. They are likely to be those patients with either multiple medical problems or a dementing illness referred for consultation and care. Thus, a significant selection bias would OCN in using the nondemented patients for thig group as controls to look at the relative health of Alzheimer patiehts. I would question the use of the non-Alzheimer dementia patients as a control group. The authors did n@ provide data supporting that the Alzheimer patients and the non-,Alzheimer dementia patients had similar ability to report symptoms. A diminished capacity to report symptoms would decrease identification of some diseases. The finding that the Alzheimek patients took fewer medications than the control groups was interpreted as substantiating the findings of less disease in the Alzheimer youp. An alternative and plausible explanation for this finding is that fear of exacerbating a preexisting dementia may have tempered p w b i n g habits. Finally to explain their results the authors offer as a ”provocative hypothesis . . . the loss of recall and understanding in Alzheimer patients might decrease the mental stress of life” and thus be protective against disease where stress +y play a role. Iquestion the validity of this proposal. My experience with demented patients has been that confusion can result in considerable fear and anxiety, thus increasing rather than diminishing the stresses suffered by the patient.

When Asymptomatic Bacteriuria is not Asymptomatic or “Pseudo-Urinary Tract Infection”

To the Editor: Symptomatic urinary tract infection (UTI) requires differentiation from so-called asymptomatic bacteriuria, for which treatment in older individuals is generally not indicated (1). Treatment of the latter may be considered contraindicated given the potential for antibiotic side effects, emergence of resistant bacteria, further urological studies and associated iatrogenesis, and costs. Thus, truly differentiating UTI from asymptomatic bacteriuria relies on the presence of no symptoms, which is implicit in the term “asymptomatic.” Nevertheless, clinicians often face clinical syndromes in the setting of abnormal urinary findings and therefore treat the urinary findings as if bacterial infection of the urinary tract is the cause of the clinical syndrome. The syndromes often include symptoms such as fever, delirium, cognitive changes, pain, falls, dehydration, and other nonspecific presentations. These syndromes tend to be more frequent in individuals with cognitive impairment and frail older nursing home residents. The classic signs and symptoms of UTI, including urinary frequency, urgency, dysuria, hematuria, and suprapubic discomfort and tenderness, often fail to accompany these syndromes, yet a diagnosis of UTI is made. The practice of antibiotic prescribing often continues despite recommendations to the contrary, and the diagnosis invoked despite the ambiguity of the term “UTI”. The limited choice for terminology (urinary tract infection versus asymptomatic bacteriuria) compound the challenge. The problem is that the patient may not be asymptomatic; the patient may be both symptomatic and bacteriuric, yet the bacteriuria often has no relationship to the clinical syndrome. At initial clinical presentation and when the need for clinical decision-making arises, one may not be certain of the role of bacteriuria or whether it needs to be treated. Experienced geriatricians will recognize that UTI may be a diagnosis of exclusion and that the urine ought to be examined only when there is no other apparent explanation for the syndrome. I suggest the term “pseudo-urinary tract infection” or “pseudo-UTI” used in the case of the erroneous diagnosis of recurrent urinary tract infection in one child. Like other pseudo-syndromes (pseudotumor cerebri, pseudogout, pseudoseizure, pseudohyperkalemia), this term indicates that a clinical finding or syndrome exists but that the etiology of the syndrome is not what is usually invoked as causative. In other words, bacteriuria is no more related to the syndrome than normal skin flora is to syncope. Criteria for the diagnosis of pseudo-UTI might include a clinical syndrome for which etiologies other than infection of the urinary tract are plausible, bacteriuria with or without pyuria, and resolution of the clinical syndrome with measures not specific to manipulation or treatment of urinary tract flora. Individuals might initially still undergo treatment for UTI, but at least once the clinical syndrome evolves or resolves, pseudo-UTI may be the more appropriate descriptor of the syndrome. This may also lead others to question a diagnosis of UTI if symptoms not specific to the urinary tract recur.

COX-2-dependent and independent effects of COX-2 inhibitors and NSAIDs on proatherogenic changes in human monocytes/macrophages

It is the second decade of controversy regarding the cardiovascular effects of cyclo-oxygenase-2 (COX-2) inhibitors. At this time, celecoxib is the only available COX-2-specific inhibitor for treatment of pain and inflammation. Therefore, the present study was designed primarily to determine the impact of celecoxib on cholesterol handling (uptake via scavenger receptors and efflux from the cells) and foam cell formation in human THP-1 macrophages, followed by comparison to rofecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs). THP-1 human macrophages and peripheral blood mononuclear cells were incubated with: celecoxib, rofecoxib, naproxen (at 5, 10, 25 µM) and acetaminophen (0.5 mM, 1 mM)±oxidized low-density lipoprotein (oxLDL, 25 µg/mL). Scavenger receptors: CD36, LOX-1, SR-A1, and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and G1, and 27-hydroxylase were detected. The adhesion of monocytes to cultured endothelial cells with/ without COX-2 inhibitors/NSAIDs was also analyzed. The presence of celecoxib and rofecoxib (at high concentrations) significantly decreased expression of 27-hydroxylase and ABCA1, interfering with normal cholesterol outflow from macrophages. Acetaminophen and the non-specific COX inhibitor naproxen had no significant effect on these proteins. Only celecoxib had a profound effect on the class B scavenger receptor CD36 and the class E receptor LOX1. We demonstrate that in contrast to celecoxib, rofecoxib and naproxen increased adhesive properties of monocytes to endothelial cells. This work might contribute to our understanding of multiple mechanisms underlying elevated cardiovascular risk upon the use of COX-2 inhibitors and uncover new possibilities to enhance the safety profile of existing COX-2 inhibitors.