Subject Index .^.BCD, see Amphotericin B colloidal dis¬ Antibody-targeted therapy (ATT), 367-369 persion antibody characteristics and, 373-374 Absorption kinetics antibody localization in, 369-370 of orally-administered drugs, 116 melanoma-antibody system in, 374-380 in spaceflight, 615-618 monoclonal antibody (Mab) in, Acetylcholine, and vagal activity, 61-62 367-370, 373-379, 383-384 Acid peptic disease, see Ulcer disease and toxic agents, 383-384 ACTH tumor features and, 370-373 and cell proliferation, 212 Anticancer drug activity, circadian timing and, circadian release of, 212-218 253 and adrenal target cell response, 610 Anticholinergics, 514 light cycle control of, 559 in ulcer disease, 506 ACTH plasma levels, circadian rhythm in, 535 Anticoagulant therapy, circadian changes in, Addison’s disease, and circadian treatment reg¬ 162-163 imen, 536 Antiinflammatory drug delivery, circadian tim¬ Adrenal therapy, artificial hypothalamus and, ing and, 252 252 Antiinflammatory drug effects, plasma level Adrenergic blockade, of RSA, 81, 84 variations and, 560 Adrenergic function, circadian variation in, Antithrombotic agents, chronopharmacody- 128-130 namics of, 162-163 Adrenergic receptor stimulation, circadian Arrhythmias, closed-loop delivery systems in, rhythm in, 493 252 Adriamycin Arterial embolism, circadian rhythms and, 162 circadian variations for, 106 Arthritis chronotherapy, NSAID in, 475-476 and drug-associated toxicity control, Asthma 476-478 airway inflammation in, 123-127 pharmacologic changes in, 110 circadian rhythm in, 131-132 A^, see a Fetoprotein chronophysiologic determinants of, 123-135 Age-related changes chronotherapy for, 472-473, 533 in chronokinetics, 107-108 in RSA, 72-75 circadian aspects of, 123-127, 467 in testosterone levels, 443 circadian rhythms in AIDS, see Immunodeficiency syndromes and drug therapy, 558 Airway inflammation and pathogenesis, 123, 132-135, 490-493 in asthma, 123-127 corticosteroid treatment of, 490 circadian rhythm in, 131-132 drug regimen compliance in, 530 Allergic disease drug therapy, cell periodicity neurohumoral circadian rhythms and, in, 558 491-492 Allergic rhinitis, rhythmic fluctuations in, 467 nocturnal Alzheimer’s disease, site-specific drug delivery airway cooling and, 135 in, 536 bronchodilator medication timing and, Amenorrhea, see Hypothalamic amenorrhea 134 Amphotericin B colloidal dispersion (ABCD), circadian rhythms and, 123, 132-135, therapeutic index of, 586-587 490-493 Analgesia, patient-controlled, 544-545, exogenous factors related to, 132-135 599-600 gastroesophageal reflux and, 134 Anesthesia, vagal tone and, 62 impaired mucociliary clearance and, Anesthetics, circadian time dependency of, 559 134-135 Angina incidence of, 490-91 circadian pattern in, 53-54 mechanisms postulated, 491-493 rhythmic fluctuations in, 467 sleep and, 132-134 Anosmia, in IHH, 553 snoring and, 134 Antacids, in ulcer disease, 505-506 pulsed corticosteroid dosage in, 571 Antibody-targeted photolysis (ATPL), theophylline chronotherapy of, 493-498, 383-391 566-568 629 630 ANNALS NEW YORK ACADEMY OF SCIENCES ATPL, see Antibody-targeted photolysis circadian pharmacokinetics and, 221 Atropine cytokinetic rhythms in, 229-232, 257-275 differential temporal kinetics of, 613-614 Cancer/host balance RSA effect of, 81-83 circadian rhythms and, 228-253 temporal plasma level changes in fertility cycle and, 230-232 and CNS impairment effects, 613-614 seasonal changes in, 229-230 and GH, 613-614 Carcinogenesis, circadian rhythms and, 229 and heart rate, 613-614 Cardiac transplantation, RSA and, 75-76 ATT, see Antibody-targeted therapy Cardiovascular active drugs, see also specific Automatic drug-delivery systems, see Drug- drugs delivery systems chronopharmacokinetics of, 166-179 circadian rhythms and, 168-179 13ayesian feedback-controlled therapy, 570 Cardiovascular age evaluation, RSA and, BGL, see Blood glucose level 67-68 Biological clock, see Circadian rhythms Cardiovascular events Biological rhythms, 1, see also Circadian chronopathology of, 161-163 rhythms; Circamensual rhythms; circadian pattern in, 53 Circannual rhythms; Circaseptan Cardiovascular function rhythms circadian rhythms in, 166-168 circadian enzymatic regulation of, 357 during pregnancy, 619-621 in Drosophila, 1-3, 6-9 Cell cycle perturbation, and drug resistance, features of, 465-466 274-275 gene influence on, 3 Cell cycles Biophysical rhythms, 229 circadian gating in, 246-248, 258 Biotherapy, implanted closed-loop drug deliv¬ host/cancer balance in, 258-259 ery systems in, 252 Cell function modification, circadian rhythms Blood glucose level (BGL), control of, 596 in, 558 Blood pressure Cell implants, and drug delivery, 394-402 ambulatory monitoring (ABPM) of, 38-54 Cell proliferation circadian rhythms in, 619-621 circadian gating of, 271-274 monitoring of, 39-41, 44-48 circadian rhythms in, 182-204 circaseptan rhythms in, 621 experimental design importance of, ultradian rhythms in, 44-50, 52-54 212-218 Bone marrow cells hormonal influence on, 207-212 DNA synthesis in and host drug susceptibility, 218-221 circadian rhythms in, 605, 608-609 in intestinal tract, 191-204 cortisol and, 608-609 phase shifting of, 206-207 proliferation of synchronization of, 204-206 circadian rhythms in, 191-192 circadian stage dependency of, 560 Breast cancer, fertility cycle and, 229-230 melatonin inhibition of, 624 Breast cancer surgery perturbation of, 270-271 menstrual cycle and, 230-289 rhythmicity in, 559-560 Bronchial patency, circadian rhythm in, surgical modulation of, 268-269 124-127 ultradian gating of, 271-273 Bronchial responsiveness, circadian variation Cell proliferation phase in, 131, 491-492 surgery effects on, 267-268 Bronchodiiator medication Cell receptor fluxes, and PK changes, 558 circadian timing and, 134, 252 Cell susceptibility/response, circadian rhythm Burst release, of drugs, 578-579 in, 558, 561 Central nervous system (CNS) O'alcium channel blockers, chronopharma- circadian neuropeptide rhythms in, 537 cokinetics of, 176-179 PK changes and, 558 Cancer site-specific drug delivery to, 536-537 biotherapy in, 252 Central nervous system impairment and circadian timing, 353 atropine levels and, 613-614 chemotherapy in Cerebral infarct, rhythmic fluctuations in, 467 and bone marrow suppression, 605 Cerebrovascular events, chronopathology of, cytokinetic-directed, 257-259 161-163 SUBJECT INDEX 631 Chemotherapy Chronoradiotherapy, 485 ambulatory pumps for, 544-545 Chronotherapeutics, see Chronotherapy and cell proliferation circadian rhythms, Chronotherapy, 110-113, 116-117, 465-467, 182-221 478-479, 485 and cell proliferation perturbation, 270-271 approaches in, 113 chronochemotherapy in asthma, 493-498 FPsin, 351-358 biological markers and, 570 circadian timing in, 253 biologic response modifiers in, 322-323, 325 and cytotoxicity, 292-307 case histories in, 474-478 and infusion, 350-351 chronobiology and, 563 cytokinetic-directed, 257-259, 261-271 circadian, 235-248 and DNA synthesis, 258-259 and programmable drug-delivery devices, CHF, see Congestive heart failure 559 Cholinergic tone, circadian rhythmicity of, constraints in, 118-120 130-131 drug choice in, 117 Chronergy, 102, 110 drug-specific, 517 Chronesthesy, 102, 108-109, 467-468, 479 in human cancer, 485-486 and chaotic oscillations, 110 individualization of, 564, 570 Chronic obstructive pulmonary disease investigative protocols for, 465-479 (COPD) model regimens in, 569-571 circadian influences in, 492-493 in nonasthmatic COPD, 492-493 theophylline chronotherapy in, 498-501 PD considerations in, 118 Chronobiology, 228-229, 257-259, 428, protection timing in, 486 478-479 research/development of, 468 basic principles of, 465-468 social event timing and, 568-570 and cancer etiology, 229 and temporal drug action control, 120-121 and chronotherapy, 563-565 testing protocols for, 468-471 compliance problems, 565-568 theophylline in, 472-473, 493-501 day-ni^t cycle in, 604 Chronotolerance, of anticancer agents, drug industry and, 484-488 110-111, 113 and drug therapy optimization, 563-564 Chronotoxicity, 292 and homeostasis, 604 and antiinflammatory drug chronopharma¬ and medical practice, 252 cokinetics, 560 multioscillatory model basis of, 604 of chemotherapy, 301-303 PK changes in, 558 of cisplatin/analogues, 296-299, 302 and prevention, 488 of doxorubicin, 295-296, 302 research limitations in, 564 of drug combinations, 299, 302-303 role in chronotoxicity of, 558 of FPs, 293-295, 301-302 and therapeutic timing, 568-570 Chronotoxicology Chronochemotherapy, see under Chemo¬ circadian drug timing and, 294-299, therapy 558-561 Chronocytokinetics, 304-306 light-dark cycle and, 559 Chronokinetic changes Cimetidine, 157, 504, 506-514, see also H2 re¬ in drugs, 102-106 ceptor antagonists sex/age-related, 107-108 Circadian change Chronokinetics, 102, 106, 467, 479 in anticoagulant therapy, 162-163 Chronopathology, 467, 479, 485 chronokinetic, 102-103 of cardiovascular/cerebrovascular events, in colon activity, 143 161-163 in drug plasma levels, 105-106 Chronopharmacodynamics, 485, 558 in gastrointestinal pH, 142, 150-152, of antithrombotic agents, 162-163 154-157 of cardiovascular-active drugs, 166-179 in hemostatic system, 159-161 Chronopharmacokinetics, 304, 485 in serum IgE, 131 and cancer treatment, 221 in thrombolytic rtPA response, 163 of cardiovascular active drugs, 169-179 Circadian cytokinetics, and cancer treatment, Chronopharmacology, 466-467, 484-85, 558 221 and circadian rhythms, 102 Circadian dosage control, and prednisolone of drug toxicity, 257-259 efficacy, 560 632 ANNALS NEW YORK ACADEMY OF SOENCES Circadian dynamics in CNS neuropeptides, 537 of coagulation, 159-161, 163 in coronary heart disease drug therapy, 558 of gastric acid secretion, 150-157 in corticosteroid blood levels, 560 Circadian enzyme regulation, of biological and cortisol/DNA synthesis covariation, clock, 357 605, 608-609 Circadian gating, of cell proliferation, 271-273 and cortisol levels, 492, 563 Circadian modulation, of cell kinetics, 257 in Cushing’s disease, 535-536 Circadian pattern and cytotoxic chemotherapy, 292-307 in cardiovascular catastrophes, 53 in diabetes therapy, 558 of drug response, 602 in dose timing, 530 Circadian-patterned infusion in Drosophila and drug toxicity, 238-241 eclosion, 1-2 and FUDR therapeutic index, 236-237 genes influencing, 1-7 in renal cell carcinoma, 241-243 and per protein, 2-3 Circadian profile, in multiple drug delivery, 547 in drug delivery Circadian rhythm(s), 108, 110-111, 113, 428, of antiinflammatory drugs, 252 465 and FP cytotoxicity, 350-351 in Addison’s disease, 536 of Hj blocking agents, 252 in adrenergic function, 128-130 and therapeutic index, 292 in airway inflammation, 131-132 and drug release/absorption, 140-141 in allergic disease drug therapy, 558 and drug responsiveness, 602 and anesthetics, 559 in dyspnea, 124 and antigen recognition, 314 in dystonia, 536 and antihypertensive therapy, 38-54 and enzyme regulation, 357-358 and arterial embolism, 162 in epinephrine levels, 492 in asthma, 466, 490-493 in erythropoiesis, 610 in asthma drug therapy, 558 Circadian rhythm(s), continued and automated drug-delivery systems, in FEV,, 491-493 249-253 in gastric acid secretion, 150-151, 504, 514 Circadian rhythm(s), continued in heart rate, 619-621 and bone marrow cell DNA synthesis, 605, in hepatic drug metabolism, 560 608-609 in hormone secretion/release, see specific in bronchial hyperreactivity, 131 hormones in bronchial patency, 124-127 and host/cancer balance, 228-252 in bronchial responsiveness, 491-492 and host susceptibility, 218-221 and calcium channel blocker PK, 176-179 and hypercoagulability, 163 cancer chemotherapy and, 257-259 in hypertension drug therapy, 558 and cancer etiology, 229 in immune system, 232-234, 312-325 and cardiovascular-active drugs, 168-179 and immunity time structure, 320-321 in cardiovascular/cerebrovascular events, in lung water, 492 161-179 and lymphocyte blood release, 318-320 in ceil cycle gating, 246-248 and lymphocyte proliferation, 317-318 and cell function modification, 558, 561 mutation and, 7-9 in cell proliferation, 183, 188-189, 559 and myocardial infarction, 161, 167 ACTH and, 212 in neurohumoral levels, 491-492 EGF and, 208, 210 in neurotransmitter receptor binding, 537 and experimental design, 212-213, 215, in nocturnal asthma, 123, 132-135 218 in nonasthmatic COPD, 492-493 gating of, 271-273 and optimized infusion costs, 248 glucagon and, 210-211 in pain, 537 and host drug susceptibility, 218-221 in patient-controlled analgesia, 599 insulin and, 210-211 pharmacokinetics and in intestinal tract, 191-196, 199-204 in PEER, 492 phase-shifting of, 206-207 and per protein, 2-3 synchronization of, 204-206 in pineal gland activity, 22 and cell susceptibility/response, 561 PK and in cholinergic reflex mechanisms, 130-131 in cardiovascular active drugs, 166-179 SUBJECT INDEX 633 during pregnancy Closed-loop drug-delivery systems, see under in blcxxl pressure, 619-621 Drug-delivery system(s) in heart rate, 619-621 CNS, see Central nervous system in psychotic states drug therapy, SS8 Colorectal cancer, profiled drug delivery in, of receptors, 109 546 in renal plasma flow, 558 Compliance, and therapeutic response, in serum IgE, 131 566-568 and sudden cardiac death, 161 Compliance-response relations in T cell activity, 315-317 of drug dosing, 527-529 in testosterone levels, 442-443 in hypercholesterolemia medication, 528 age efiect on, 443 Congestive heart failure (CHF), RSA ampU- and therapeutic response, 563, 566-568 tude and, 85-90 and thrombotic stroke, 161 Constant-rate drug delivery, see 2^o-order in tumor cell DNA synthesis, 264-267 drug delivery in vagal activity/tone, 492-493 Contraception, see Oral contraception Circadian stage COPD, see Chronic obstructive pulmonary and adrenal target cell response, 610 disease RSA and, 72 Coronary heart disease, circadian drug therapy and T cell activity, 315-320 in, 558 Circadian stage dependency, of cell prolifera¬ Corpus luteum maintenance regimens, tion, 560 554-556 Circadian time dependence, of anesthetics, 559 Corticosteroid blood levels, diurnal rhythm in, Circadian timing 560 and anticancer drug activity, 253 Corticosteroids and antiinflammatory drug administration, in chronotherapy, 471-472, 485-488 252 optimum therapy and, 564 pulsed dosing of, 571 Circadian treatment regimen, in Addison’s dis¬ Cortisol ease, 536 circadian release of, 28, 35, 50, 605-609 Circadian variation circannual rhythms in, 441 “controlling” for, 568 and DNA synthesis, 605-609 and experimental design, 212-218 plasma levels of, 128, 492, 535-536, 563 in inflammatory cell influx, 492 Cushing’s disease, hormonal circadian rhythms in inflammatory mediator release, 492 and, 535-536 in pharmacokinetic parameters, 560 Cyclic AMP, circadian rhythmicity of, 130 in SOL, 610 Cytokinetic rhythms, 351 Circamensual periodicity, and immunity, in cancer, 257-278 321-322 in chemotherapy, 257-259 Circamensual rhythm(s), 465 Cytotoxic agents, therapeutic index of, and breast cancer surgery, 230-232,277-289 292-307 in hormone levels, 442 Circannual rhythm(s) ]Day-night cycle, in homeostasis, 604 in cardiovascular/cerebrovascular events, Diabetes, see also Juvenile diabetes 162 circadian drug therapy in, 558 in hormone levels, 441-442, 445 onset seasonality in, 602 Circannual time structure, of immunity, 320 Diastolic cardiac function, RSA and, 77-79 Circaseptan rhythm(s) Disease, see also specific diseases in hormone levels, 442 and PK changes, 558 and immunity, 321-322 rhythmic fluctuations in, 467 during pregnancy, 619-621 DNA synthesis Cisplatin chemotherapy and, 259-267 chronotoxicity of, 302-303 circadian variation in, 258-261, 605-609 circadian drug timing of, 235, 534 cortisol covariation with, 605-609 and drug-associated toxicity, 476-478 host/cancer cell cycles and, 258-259 programmable implanted delivery of, 542 phase relationship of, 264-265 Cisplatin cytotoxicity Dose compliance, see Compliance; Drug regi¬ circadian drug timing and, 296-299 men compliance 634 ANNALS NEW YORK ACADEMY OF SCIENCES Dose-response curve characteristics, in secre¬ liposomal, 362-365, 572-574, 589-591 tory/receptor mechanisms, 29 localized, 409-411 Dose timing, 529 magnetically controlled, 330-331 and cholesterol synthesis inhibitors, 530 and multiple drug delivery, 547 circadian rhythm in, 530 oral, 410-411, 414-415, 435-37, 439 and drug effectiveness, 560 Egalet* system, 578-580 Down regulation, 31-32, 34-35 OROS* systems, 435 receptors and, 35 parenteral, 429, 431-433 Doxorubicin, 67, 485, 538 patient-controlled, 544-545, 599-600 chronotoxicity of, 302-303 patterned, 428-439 and circadian treatment time, 235, 534 in periodontal therapy, 410-411 cytotoxicity of, 295 profiled, 546-547 circadian drug timing and, 295-296 Drug-delivery system(s), continued programmable implanted delivery of, 542 programmable, 533-542, 545-546 RSA effect of, 84-91 zero-order release in, 578-579 Drosophila, circadian rhythms in, 1-8 programmable implanted Drug absorption MiniMed Implantable Infusion System, food effect on, 145-146 539-541 physiological factors in, 140-145 PIMS, 535, 539 and release, 140-142 SynchroMed* Infusion System, 534-535, in spaceflight, 615-618 541 temporal aspects of, 140, 146-147 programmed, 428-435, 439 Drug-associat^ toxicity, 476-478 burst release in, 578-579 Drug delivery, see also Drug-delivery systems and circadian chronotherapy, 559 arterial pulsatile, 428-429, 433, 439, 549 of FPs, 348 site-specific, 536-537 PD of, 347-348 targeting in, 572-574 PK of, 345-347, 349 temporal control in, 460-463 temporal patterns of, 348-349 therapeutic systems concept and, 405-409 burst release in, 578-579 transdermal/transcutaneous, 411-412, 414, circadian-modified transcutaneous, 252 433-435 feedback-controlled, 434-435 triggered, 428, 436-439 by genetically engineered cell implants, ultrasonically controlled, 331-332 394-402 variables in, 604 receptor dynamics in, 518-521 Drug dynamics, in spaceflight, 615-618 of sex steroids, 518-521 Drug effectiveness, administration time and, signal-sensitive, 362-365 560 targeted, 335-336, 428, 536, 572-574 Drug regimen compliance temporal, 146-147, 504-514 dose timing and, 529-530 benefits of, 425-426 electronic monitoring of, 522-526 engineering perspective, 422-424 Drug release, 140-141 Drug-delivery system(s), see also Drug delivery by lysosomal enzymes, 336-338 Drug-delivery system(s), see also Zero-order modified, 578-579 drug-delivery systems non-zero-order, 584-585 ambulatory pumps in, 544-547 Drug resistance, cell cycle perturbation and, artificial hypothalamus, 252 274-275 pulsatile release in, 549 Drug responsiveness, circadian pattern of, 602 automatic, 249-253 Drug susceptibility, cell proliferation circadian circadian rhythms and, 253, 428-429, 433 rhythms and, 218-221 closed-loop Drug therapy and endocrinology, 252 cell periodicity in, 558 fetus/placenta as, 619-621 optimization of, 563-564, 570 colon-targeted, 429, 435-439 Drug tolerance, and PK changes, 558 conductive polymers in, 592-594 Drug toxicity, 239-240, 292-299, 301-303, controlled release, 575-576, 578-585 558-561 enzymatically controlled, 332-333, 335-338 Drug toxicity, and delivery time, 560 implanted, 535, 539-541, 545-546 Dyspnea, in COPD, 492, 498 SUBJECT INDEX 635 Dystonia Feedback techniques, in diurnal variation as¬ circadian rhythm in, 536 sessment, 117 site-specific drug delivery in, 536 Fertility cycle, see also Menstrual cycle and breast cancer/host balance, 229-230 Elclosion and breast cancer surgery, 230-289 circadian rhythms and, 1-2 Fertility problems, circadian-patterned therapy genes for, 3-7 in, 252 EGF, see Epidermal growth factor a Fetoprotein (AFP) Electrotransport drug-delivery systems, biological growth activities of, 623 433-435, see also lontophoretic drug and estrogen-sensitive cells, 623-626 delivery Fetus-placenta, as closed-loop drug-delivery Emotional disorders, circadian-patterned ther¬ system, 619-621 apy in, 252 FEV„ see Forced expiratory volume Endocrine circadian rhythms Fluorodeoxyuridine (FUDR/FdUrd) and cell function modification, 558 arterial delivery of, 345-351 and cell susceptibility/response, 561 chronopharmacology of, 243-246 Endocrine networks, intermittent hormone re¬ chronotoxicity of, 239-240, 301-302 lease in, 11 circadian administration of, 236-243, Endocrinology, closed-loop drug delivery in, 350-357, 534 252 in circadian cell cycle gating, 246-248 Endometrium PD of, 243-246 breakthrough bleeding in, 519-520 programmable pump infusion of, 534-535, HRT control and, 519 539, 542 hyperplasia in, 519-520 Fluoropyrimidines (FP) stability of, 518 arterial delivery of Environmental factors, variable responsiveness PD of, 347-348 to, 602 PK of, 345-347 Enzymes chronotoxicity of, 292-299, 301-303 and biological clock regulation, 357 circadian-dependent metabolism of, 350-358 and drug release, 332-333, 336-338 cytotoxicity of, 293 and FP chronochemotherapy, 351-357 circadian drug timing and, 294-295 Epidermal growth factor (EGF^ temporal delivery patterns of, 348-349 and circadian cell proliferation, 207-210 therapeutic index of, 350-357 release of, 208-210, 215 Follicle stimulating hormone (FSH) in ulcer disease, 210 circannual rhythms in, 441-442, 445 Epilepsy, rhythmic fluctuations in, 467 in GnRH abnormalities, 549-550 Episodic hormone release, see under Hormone pulsatile release of, 17, 19-20, 25, 548 release Follicle-stimulating hormone (FSH) E^-responsive breast cancer cells, inhibition of, pulsatile release of, 12, 15, 17, 19 624 Forced expiratory volume (FEV,) Erythropoiesis, circadian rhythm in, 610 in asthma, 491 Erythropoietin, circadian hematocrit response circadian rhythm in, 491-493 to, 610-612 theophylline chronotherapy and, 496-498 Estradiol, in GnRH abnormalities, 549 FP, see Fluoropyrimidines Estrogen FSH, see Follicle stimulating hormone HDL effect of, 519 FUDR, see Fluorodeoxyuridine receptor kinetics and, 518-521 transdermal delivery of, 414, 428 Orastric acid patterns circadian rhythmicity of, 150-151, 504, 509 Famotidine, 157, 508, 513-514, 517, see also and drug absorption, 142 Hj receptor antagonists Gastric pH patterns FdUrd, see Fluorodeoxyuridine under Hj receptor antagonist blockade, Feedback 152-157 Bayesian, 570 Gastroesophageal reflux, nocturnal asthma in glucose homeostasis, 29, 31-34 and, 134 in RSA vagal inhibition, 59 Gastroesophageal reflux disease (GERD), Feedback-controlled drug delivery, 434-435 chronotherapy in, 517 636 ANNALS NEW YORK ACADEMY OF SOENCES Gastrointestinal motility Homeostasis in drug absorption, 142-143 day-night cycle and, 604 Gastrointestinal pH and dose-response curve characteristics, 29, in drug absorption, 142 31-32 Gastrointestinal tract physiology, rhythmic heliogeophysical factors and, 604 fluctuations in, 467 insulin in, 29, 32-33 Gastrointestinal transit and secretion-reaction time lags, 32-34 in drug absorption, 143-145 Hormonal mechanisms, and PK changes, 558 Gating Hormone levels circadian cell cycle, 246-248, 258 circadian rhythms in, 442-443 of tumor cell DNA synthesis, 258-265 circannual rhythms in, 441-442 ultradian, 271-274 monthly/weekly rhythms in, 442 GERD, see Gastroesophageal reflux disease Hormone pulse detection, methods for, 13-15 GH, see Growth hormone Hormone release, see also specific hormones Glaucoma, diug regimen compliance in, 530 episodic, 12 Glucagon intermittent, 11-25 and circadian cell proliferation, 210-211 pulsatile, 28-36 release of, 28, 210-211 ultradian, 12-15 GnRH, see Gonadotropin release hormone in hypothalamohypophyseal-gonadal axis, Gonadotropin release hormone (GnRH) 15-21 abnormalities in, 548-549 Hormone replacement therapy (HRT) and anosmia, 553 artificial hypothalamus in, 549-556 pulsatile release of, 15-21, 25, 50, 548 endometrial hyperplasia in, 519-520 Growth hormone (GH) receptor dynamics and, 519-521 diurnal rhythm in, 535-536 receptor dynamics in, 519-520 release of, 28, 559 regimens in, 518 Growth hormone (GH) levels, atropine plasma therapeutic considerations in, 518-519 levels and, 613-614 Host/cancer balance Growth problems, circadian-patterned therapy DNA synthesis and, 258-259 in, 252 seasonal changes in, 229-230 Hj Receptor antagonists Ha, see Hypothalamic amenorrhea in chronotherapy, 474-475 H2 blocking agents, circadian timing and, 252 dosage regimens for, 506-514 HDL, see High density lipoproteins in GERD, 517 Heart rate rhythms in ulcer disease, 506-514 atropine plasma levels and, 613-614 in Zollinger Ellison syndrome treatment, 506 drug response of, 57-58 Hj Receptor blockade, gastric acid secretion neural mechanisms of, 58 under, 150-157 during pregnancy, 619-621 HRT, see Hormone replacement therapy and vagal tone, 57-59 Hypercholesterolemia, compliance-response Heart rate variability assessment, 98-99 in, 528 Heliogeophysical factors, and homeostasis, 604 Hypercoagulability, circadian rhythms and, Hematocrit, circadian-dei>endent response in, 163 610-612 Hyperglycemia, pulsatile insulin release and, Hematology, and automatic drug-delivery sys¬ 33-34 tems, 252 Hyperlipidemia, in oral contraception therapy, Hemostatic system, circadian changes in, 518-519 159-161 Hyperplasia, endometrial, 519-520 Heparin Hypertension circadian variations for, 106 circadian drug therapy for, 558 pharmacologic changes in, 110 closed-loop drug-delivery systems in, 252 Hepatic drug metabolism, diurnal rhythm in, ultradian rhythms in, 38-54 560 Hypoglycemia, 35 High density lipoproteins (HDL) pulsatile insulin release and, 32-34 estrogen and, 519 Hypogonadism and oral contraception therapy, 518-519 LH/FSH levels in, 445 Histamine, circadian rhythmicity of, 130 testosterone levels in, 444-445 SUBJECT INDEX 637 Hypothalamic amenorrhea (HA), 548-552 Infusion pumps, 428-429 Hypothalamic control, and pulsatile hormonal adverse reactions to, 555 release, 548 pulsatile delivery via, 549, 553-555 Hypothalamohypophyseal-gonadal axis, 11 Infusion treatment ultradian hormone release in, 15-21 in cancer chemotherapy Hypothalamus circadian shape of, 350-351 artificial circadian optimized costs of, 248 in endocrinology, 252 with FUDR, 236-241, 243-244, 246 pulsatile delivery by, 549 and implanted drug-delivery systems, and hormone release, 11-21 534-535 and hormone release control, 548 Insulin, 29, 31, 35 ambulatory pump delivery of, 544 and circadian cell proliferation, 210-211 iontophoretic transdermal delivery of, 450, Idiopathic hypogonadotropic hypogonadism 461-463, 596-597 (IHH), 548-553 programmable delivery of, 535 anosmia in, 553 pulsatile secretion of, 28-36, 50, 210-211, IHH, see Idiopathic hypogonadotropic hypo¬ 535 gonadism and hyperglycemia, 33-34 Immune surveillance, circadian-adapted, and hypoglycemia, 32-34 313-325 Insulin resistance, 31-32 Immune system, and circadian rhythms, in receptor/postreceptor mechanisms, 34-35 232-234, 314-322 Intestinal tract, circadian cell proliferation in, Immunity time structure, circadian rhythms 191-196, 199-204 and, 320-321 Intraarterial drug delivery, in transplant ther¬ Immunoconjugates apy, 537 monoclonal antibodies in, 383-386 Intrathecal drug infusion, 536 in phototherapy, 384-391 Iontophoresis, in transdermal drug delivery, Immunodeficiency syndromes, biotherapy in, 450-463, 596-597 252 Iontophoretic transdermal drug delivery Immunoglobulin E (IgE) serum levels, circa¬ (iTDD), 450-459, see also Electro¬ dian change in, 131 transport drug-delivery systems Immunologic circadian rhythms, 232-234 electronic control of, 450-463 and cell function modification, 558 of hormones, 460-463 and cell susceptibility/response, 561 Iontophoretic transdermal drug-delivery Immunologic fluctuation, menstrual cycle (iTDD) systems, temporal control of, stage and, 277, 288 460-463 Immunosuppressants, intraarterial delivery of, Isoproterenol, RSA and, 80-83 537 IVOS* drug-delivery system, 432 Immunosuppressive drug regimens, compli¬ ance with, 530 Juvenile diabetes, onset seasonality in, 602, Immunotherapy, synchronous DNA synthesis see also Diabetes in, 259 Implanted drug-delivery systems, see under Drug-delivery systems IClinefelter’s syndrome (KS), testosterone re¬ Inflammatory cells influx, circadian variation placement in, 444-445 in, 491-492 Inflammatory mediators release, circadian Ldl, see Low density lipoprotein variation in, 491-492 LH, see Luteinizing hormone Infusion Liposomes in drug delivery, 572-574 circadian-patterned pharmacological effect of, 589-591 and drug toxicity, 238-241 and oral drug availability, 589-591 and renal cell carcinoma, 241-243 and signal-sensitive drug release, 362-365 and therapeutic index, 236-237 Low density lipoprotein (LDL) reduction, Infusion patterns compliance-response in, 528 circadian cell cycle gating and, 246-248 Luteinizing hormone (LH) in FUDR treatment, 236-246 circannual rhythms in, 442 638 ANNALS NEW YORK ACADEMY OF SCIENCES in GnRH abnormalities, 549-SSO, SS3 Mutations pulsatile release of, 12-25, 28, 548 circadian rhythms and, 1-3 Luteinizing hormone releasing hormone and neuroanatomical changes, 7-9 (LHRH) Myocardial infarction, circadian rhythms in, pulsatile delivery of, 460-461 53-54, 161, 167, 467 transdermal delivery of, 461 Myocardial ischemia, circadian pattern in, Lymphocyte blood release, circadian rhythms 53-54 and, 318-320 Lymphocyte proliferation, circadian rhythms ^Jephrotoxicity, of ABCD, 586-587 and, 317-318 Neurohormonal control, of reproduction, Lysosomal enzymes, and anticancer drug re¬ 553-556 lease, 336-338 Neurohormonal replacement therapy, pulsatile delivery system in, 548-556 Neurohumoral circadian rhythms, in asthma, 491-492 IVlarker rhythms, biochemical/phaimaco- Neurohumoral processes, circadian change logical, 300 and, 128-132 Melatonin Neurological diseases, site-specific drug deliv¬ cell proliferation inhibition by, 624 ery in, 536-537 ultradian release of, 21-25 Neurotransmitter receptor binding, circadian Menarche, seasonality in, 602 rhythm in, 537 Menotropin therapy, for ovulation induction, Nonsteroid antiinflammatory drugs (NSAID), 556 in arthritis chronotherapy, 475-476 Menstrual cycle NSAID, see Nonsteroid antiinflammatory and breast cancer surgery, 230-232,277-289 drugs and natural killer (NK) cell activity, 277, 288, 321-322 MESOR, see Midline estimating statistic of ^)ral contraception rhythm breakthrough bleeding in, 519 Methotrexate, programmable delivery of, 542 drug regimen compliance in, 530 Midline estimating statistic of rhythm HDL levels in, 519 (MESOR), 486 Oral drug-delivery systems, 435-436 Monoclonal antibodies (Mabs) colon-targeted, 429, 436-437, 439 immunoconjugates of, 383-391 liposomes in, 589-591 and phototherapy, 384, 389-391 modified drug release in, 578-579 and toxic agent targeting, 383-384 Organic nitrates, chronophaimacokinetics of, Monoclonal antibody (Mab) therapy, 367-370, 171-176 373-379, 383-384, see also Osteoarthritis symptoms, rhythmic fluctua¬ Antibody-targeted therapy (ATT) tions in, 467 Ovulation induction Morphine in patient-controlled analgesia, 599-600 menotropin therapy for, 556 site-specific delivery of, 536 regimens for, 549-554 Morphine dosage PK and, 581-582 Pain and programmable drug-delivery systems, circadian rhythm in, 537 581-582 site-specific drug delivery in, 537 Morphine utilization, temporal variation in, Pancreas therapy, artificial hypothalamus in, 599-600 252 Mucociliary clearance, nocturnal asthma and, Parasympathetic blockade, of RSA, 81 134-135, 491 Parenteral drug delivery, 429, 431-33, 479 Mucociliary transport, theophylline chrono- self-formulating in-line system, 429,431-433 therapy and, 493 Parkinson’s disease, site-specific drug delivery MultifrM]uency host/cancer balance, 228-253 in, 536 Multioscillatory chronobiology model Patient-controlled analgesia, 544-545 temporal variation in, 599-600 temporal variation in, 599-600 Multiple sclerosis, site-specific drug delivery in, PCO, see Polycystic ovary syndrome 536 PD, see Phaimacodynamic(s)