bluuebunny/crossref_metadata_2025 huggingface dataset:
The Application of Stable Isotopes to Studies of Drug Bioavailability and Bioequivalence
Authors: Wolen Robert L.
Published: March 2013

The increased availability of chemical intermediates and automated instrumentation has resulted in expanded use of stable isotopes for bioavailability and bioequivalence studies in recent years. Initially, stable isotopes were confined to the labeling of mass internal standard compounds for gas chromatography/mass spectrometry. More recently, their in vivo use has expanded and proved to be a powerful pharmacologic tool. The lack of toxicity of stable isotopes, particularly deuterium and carbon‐13, make them ideally suited for human studies. The primary advantage of the isotopic methods is that the drug can be administered concomitantly either by two routes (e.g., parenteral and oral) or in two formulations (e.g., solution and solid dosage). Thus, a single set of blood samples serves to describe the time course of the routes or formulations being compared. The concomitant administration reduces variability inherent in dual administration, the single assay for both forms further reduces variation, and the method minimizes both drug exposure and discomfort to the subject. In addition to single‐dose administration, in which two routes or dosage forms are compared, the technique is well suited to “pulse” administration, wherein the kinetics of a single dose, during multiple or chronic dosing regimens, can be compared with single‐dose kinetics.
Drug Metabolite Identification: Stable Isotope Methods
Authors: VandenHeuvel William J. A.
Published: March 2013

This paper focuses on (1) stable isotope labeling of drugs, in combination with mass spectrometry (MS)‐based methods, to facilitate the recognition and identification of metabolites and (2) the employment of stable isotope‐labeled derivatization reagents (e.g., bis‐trimethylsilylacetamide‐d18) in the structure elucidation of metabolites from unlabeled drugs via gas‐liquid chromatography‐MS techniques. In both cases, it is the so‐called isotope peak shift that permits generation of data useful for metabolite identification. Furthermore, judicious labeling of a drug permits characterization of drug‐related species (metabolites) by MS‐based recognition of isotope cluster signatures. Studies using stable isotope‐labeled drugs are exemplified by work on aminopyrine and isopropylantipyrine metabolism; examples of the derivatization peak shift approach include those from studies of timolol and cyproheptadine.
Biotransformation and Excretion: In Vivo Studies Utilizing Stable Isotopes and Nuclear Magnetic Resonance
Authors: Unkefer Clifford J.
Published: March 2013

Specific 13C labeling in combination with nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for the study of metabolism. Nuclear magnetic resonance allows both the extent and distribution of 13C labels in metabolites to be quantified without the need to isolate or degrade them. In addition, NMR is nonperturbing to living cells, allowing real‐time observation of metabolic processes. To date, the application of 13C‐NMR to in vivo studies has been confined to the study of metabolic processes in cell suspensions, perfused organs, and small animals. The continuing development of large‐bore high field magnets and surface coils will, in principle, allow in vivo metabolic studies to be extended to humans.
Pharmacokinetics: Time‐Dependent Changes— Autoinduction of Carbamazepine Epoxidation
Authors: Bertilsson Leif , Tomson Torbjörn , Tyhring Gunnel
Published: March 2013

Drugs labeled with stable isotopes have been useful to study time‐dependent changes in kinetics. Early studies suggested that carbamazepine (CBZ) may induce its own metabolism, but this could not be proved until tetradeuterium‐labeled CBZ (CBZ‐D4) was synthesized and then given to patients. CBZ‐D4 was administered to three children during long‐term treatment of epilepsy with CBZ. After 17 to 32 days of treatment, the plasma clearance of CBZ‐D4 was doubled, but during the next four months, there was no further increase, indicating that autoinduction was complete within one month. Two patients with chronic alcoholism were treated with CBZ for five days. Half of the first dose of 600 mg was comprised of CBZ‐D4. The half‐life of this CBZ‐D4 dose in the two patients (20 and 26 hr, respectively) was similar to the post‐steady‐state half‐life of CBZ (23 hr in both patients) measured later. A single dose of CBZ given one week after the last maintenance dose had a longer half‐life (46 and 45 hr, respectively), which probably is close to the disposition of the drug before starting the treatment with CBZ. This shows that autoinduction of CBZ metabolism was completed during the very first doses of CBZ. Autoinduction also disappeared rapidly after stopping the treatment. We have shown that it is mainly the epoxide‐diol pathway that is induced, both during autoinduction and after induction with other antiepileptic agents.
Pharmacokinetics: Dose‐Dependent Changes
Authors: Browne Thomas R. , Greenblatt David J. , Evans James E. , Szabo George K. , Evans Barbara A. , Schumacher Gerald E.
Published: March 2013

Stable‐isotope tracer methods are described for answering the following questions about a drug: (1) Does the drug exhibit dose‐dependent changes in pharmacokinetic properties? (2) What are the drug's Michaelis constant (Km) and maximum velocity (Vmax) for enzymatic biotransformation; (3) Are the dose‐dependent pharmacokinetic changes great enough to be clinically important? and (4) Which routes of the drug's biotransformation are responsible for the drug's dose‐dependent pharmacokinetic properties? Illustrative data are provided from tracer studies performed with a drug with dose‐dependent pharmacokinetic properties, phenytoin, and a drug that does not exhibit dose‐dependent pharmacokinetic properties, phenobarbital. The advantages and disadvantages of the described stable‐isotope methods are discussed.
Pharmacokinetic Drug Interactions
Authors: Eichelbaum Michel
Published: March 2013

Drugs labeled with stable isotopes have been successfully used in pharmacokinetic drug interaction studies. This technique provides precise information on the mechanisms responsible for drug interactions, e.g., changes in clearance due to induction or inhibition of drug metabolism, bioavailability, and volume of distribution. It offers the advantage that detailed studies on the pharmacokinetics and metabolism of a drug can be conducted in a clinical setting during steady‐state conditions, thus avoiding problems in patient management that can arise from studies in which drug is withdrawn.
Embryotoxicity of Stable Isotopes and Use of Stable Isotopes in Studies of Teratogenetic Mechanisms
Authors: Spielmann Horst , Nau Heinz
Published: March 2013

Experiments on teratogenic effects of stable isotopes from our own and other laboratories are evaluated. In the first series of investigations, the enrichment of the stable isotope 13C derived from U‐13C‐glucose was studied in mouse embryos at various stages of development, including limb buds in organ culture. Preimplantation mouse embryos incubated in vitro in 13C‐enriched medium for 48 hours showed normal development during subsequent differentiation in vitro and also in vivo after embryo transfer to foster mothers. These embryos were 15% to 20% enriched in 13C. Administration of U‐13C‐glucose to pregnant mice during organogenesis led to an increase of the absolute 13C content of the embryo for several days after the end of isotope administration, whereas the enrichment in maternal tissue decreased. No alterations of embryonic development were detected due to stable isotope enrichment Development of cultured mouse limb buds was unaffected by incubation with 82 mol% U‐13C‐glucose as judged from morphologic and biochemical criteria. The second part of the article describes the value of deuterium‐labeled drugs as probes into the mechanism of activation of teratogenic metabolites. A comparison of the pharmacokinetics as well as the teratogenicity between cyclophosphamide and some specific deuterium‐labeled analogues showed that the isotope effect observed can be related to a particular metabolic pathway crucial for teratogenic activation by this drug.
Stable Isotopes in Pharmacology Studies: Present and Future
Authors: Browne Thomas R.
Published: March 2013

Stable‐isotope techniques offer advantages over older methods in safety, sensitivity, specificity, and reduction in numbers of subjects required and analytic determinations for some types of pharmacology studies. In addition to their use as internal standards in gas chromatography‐mass spectrometry analytic methods, stable isotopes have been successfully employed in studies of absorption, bioavailability, distribution, biotransformation, excretion, metabolite identification, time‐dependent and dose‐dependent pharmacokinetic changes, drug interactions, pharmacologic changes during pregnancy, mutagenicity, and teratogenicity.
The FDA Advisory Panel's Decision on rt‐PA
Authors: Sherry Sol
Published: March 2013

Considerable dissatisfaction has been expressed over the FDA's Cardio‐renal Advisory Panel's recommendation on May 29, 1987 that approval of rt‐PA as a thrombolytic agent for the treatment of acute myocardial infarction be delayed. Justification for the Advisory Panel's action appears to be based on a lack of adequate data supporting the clinical benefit and safety of a specific therapeutic regimen of rt‐PA, i.e., its molecular form, dosage, and duration of therapy. Although not an issue in the Panel's decision, questions can be raised concerning claims that rt‐PA, in comparison to streptokinase, is a safer agent as far as bleeding complications are concerned, and is twice as effective in dissolving coronary thrombi during a period of potential clinical benefit. Also to be considered is the association of its use with a higher incidence of rethrombosis and a much greater cost.
Advances in Thrombolytic Therapy for Acute Myocardial Infarction
Authors: Topol Eric J.
Published: March 2013

There has been rapid proliferation of understanding and experience with thrombolytic therapy for acute myocardial infarction. Over the last few years, selective intracoronary infusion of lytic therapy has been replaced by intravenous administration because of the fundamental importance of time to reperfusion. Newer thrombolytic agents, such as tissue plasminogen activator (t‐PA) and acylated streptokinase (APSAC), with properties distinct from streptokinase (SK) and urokinase, have been developed and have undergone extensive clinical trial evaluation. This review will focus primarily on the recent advances in thrombolytic therapy, with particular attention to efficacy, safety, and comparative aspects of the various agents currently or soon to be available.
Blood Pressure Monitoring for Assessing the Duration of Action of Antihypertensive Treatment
Authors: Weber Michael A. , Tonkon Melvin J. , Klein Russell C.
Published: March 2013

The duration of antihypertensive action of the alpha‐adrenergic blocking agent, prazosin, was studied in 12 hypertensive patients in whom twice‐daily doses of this agent were found to be effective and well tolerated during a preliminary titration period. The patients then entered a cross‐over phase of study. On a randomized basis, they were given prazosin either twice daily for eight weeks followed by an eight‐week period in which they received the same total dose once daily (each morning), or they were given the treatment for a once‐daily period followed by a twice‐daily period. Using the conventional sphygmomanometer, there were no significant differences in blood pressures for the patients as a whole between the measurements during once‐daily dosage (measured approximately 24 hours after the last administration of drug) and those during twice‐ daily dosage (measured approximately 12 hours after the last administration); but for both methods of administration, blood pressures were signrficantly lower than pre‐treatment values. Automated whole‐day ambulatory blood pressure monitoring showed a tendency for blood pressures to be lower with once‐daily than with twice‐daily treatment during the first 12 hours after the morning doses were given, but there was a reversal of this pattern during the early morning hours preceding the next dose. However, for at least half of the patients these differences were only minimal. Thus, prazosin may be effective in some patients as once‐daily treatment, especially after several weeks of therapy. Moreover, automated whole‐day blood pressure monitoring appears to be a valuable technique for guiding dosage requirements for patients on an individual basis.
Effect of Prazosin and Beta‐Blocker Monotherapy on Serum Lipids: A Cross‐Over, Placebo‐Controlled Study
Authors: Magarian Edward O. , Dietz Albert J. , Freeman David S. , Carlson James D.
Published: March 2013

The effects of prazosin and beta‐blocker monotherapy on serum concentrations of triglycerides, cholesterol, and lipoprotein cholesterol were evaluated in 16 patients with mild to moderate essential hypertension in a single‐blind, cross‐over, placebo‐controlled study. Initially patients received a bid dose of either prazosin or a beta‐blocker sufficient to maintain a sitting diastolic pressure below 95 mm Hg. After a placebo washout, patients were placed on the alternate medication. Fasting serum samples were obtained for lipid analysis during each treatment phase. Beta‐blocker therapy was associated with undesirable changes in serum lipids as evidenced by increases in the concentration of total triglyceride (45%, P = .001), total cholesterol (4%, P = .05), LDL cholesterol (6%, P = .05) and VLDL cholesterol (21%, P = .05), and a decrease in the concentration of HDL cholesterol (‐9%, P = .05). The ratios of total cholesterol to HDL cholesterol and LDL cholesterol to HDL cholesterol also increased by 15% (P = .005) and 18% (P = .005), respectively. No significant changes in any of the serum lipids were observed during prazosin administration.
The Bioavailability and Pharmacokinetics of Guanfacine After Oral and Intravenous Administration to Healthy Volunteers
Authors: Carchman Susan H. , Crowe James T. , Wright George J.
Published: March 2013

Guanfacine is a centrally acting alpha‐2 adrenergic agonist. The absolute bioavailability, pharmacokinetics, and renal clearance of this antihypertensive drug were investigated in healthy male volunteers. Eighteen subjects received a single oral or intravenous dose of guanfacine 3 mg in a two‐way cross‐over study design. Blood samples were obtained before dosing and up to 72 hours after dosing for determination of drug levels in plasma. Additional blood samples were obtained for protein binding studies. Urine was collected and pooled for specific intervals up to 96 hours after dosing. The absolute bioavailability of guanfacine after a single oral dose was 81.1%. The elimination half‐lives were 13.8 hours and 13.4 hours after oral and intravenous administration, respectively. The volume of distribution results were approximately 6 L/kg by both routes of administration. The mean plasma protein binding results were 71.6%, not influenced by plasma concentration or route of administration. The urinary recovery of guanfacine was 44.3% after oral dosing and 50% after intravenous dosing. Renal clearance of guanfacine was 50% of total body clearance and appeared to be due to a net renal tubular secretory process.
Efficacy Without Tolerance or Rebound Insomnia for Midazolam and Temazepam After Use for One to Three Months
Authors: Allen Richard P. , Mendels Joseph , Nevins Donald B. , Chernik Doris A. , Hoddes Eric
Published: March 2013

Midazolam (15 mg) was compared with temazepam (30 mg) in a randomized, double‐blind, parallel group study. An initial screening period was followed by 3 days of placebo baseline, 4 to 12 weeks of nightly oral use of the medication and a 4‐day placebo withdrawal period. One hundred seventy‐five patients with chronic insomnia participated in this multicenter outpatient study. Because the elimination half‐life of midazolam, a new trizolobenzodiazepine hypnotic, is short (1.3‐2.2 hr) compared to temazepam's (12–16 hr), more problems with tolerance and rebound insomnia were expected to occur. Hypnotic efficacy (increased total sleep time, decreased wake time, and decreased sleep latency) was demonstrated for both medications over the entire 3‐month period without the development of tolerance, In fact, if anything, efficacy increased with time on medication, suggesting possible facilitation or “inverse tolerance” effect. On withdrawal, sleep was improved compared with baseline, suggesting partial resolution of the insomniac condition rather than rebound insomnia. These effects were both statistically and clinically significant for midazolam, with 16% to 50% improvement in sleep measures. The results of this study suggest that patients with chronic insomnia may benefit from 30 to 90 days of treatment. A three‐factor model that separates pharmacologic from behavioral and psychologic effects of hypnotics was proposed to explain these results in part.
Pharmacokinetics of Pimozide in Adults and Children with Tourette's Syndrome
Authors: Sallee Floyd R. , Pollock Bruce G. , Stiller Richard L. , Stull Stacy , Everett Geoffrey , Perel James M.
Published: March 2013

Pimozide is a neuroleptic drug with dopamine receptor and calcium channel blocking activity that is used in the treatment of Tourette's syndrome. A comparison of the pharmacokinetics of pimozide was made in children and adults with Tourette's syndrome. Seven adults (ages 23–39) and four children (ages 6–13) received a single 2‐mg oral dose of pimozide and a minimum of nine blood samples were collected over a four‐day period. Mean elimination half‐life of pimozide in children was 66 hours compared with 111 hours in adults with Tourette's syndrome. Significant interindividual variability of pimozide pharmacokinetics was found in both adults and children with Tourette's syndrome. The pharmacokinetics of pimozide in patients with Tourette's syndrome differs from that reported in adult populations with chronic schizophrenia.
Disposition of Famotidine in Renal Insufficiency
Authors: Halstenson Charles E. , Abraham Paul A. , Opsahl John A. , Chremos A. N. , Keane William F. , Matzke Gary R.
Published: March 2013

The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30–60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10–30 mL/min); Group 3, end‐stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72‐hour period. Plasma concentration‐time data demonstrated biexponential decay. The terminal elimination half‐life was prolonged in Group 3 (18.6 ± 5.7 hr) compared with Groups 1 (9.3 ± 2.3 hr) and 2 (9.7 ± 1.7 hr), P < .05. Steady‐state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLP) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLP correlated well with CLCR (CLP = 1.59 CLCR + 33.8, r = 0.830, P < .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.
Jejunal Ulceration and Stricture Due to Wax‐Matrix Potassium Chloride Tablets and Amitriptyline
Authors: Bronson David L. , Gamelli Richard L.
Published: March 2013

A 68‐year‐old woman presented with abdominal distention of several weeks duration and an acute small bowel obstruction. For several years she had been prescribed amitriptyline 150 mg/d, L‐thyroxine 100 μg/d, and digoxin 0.25 mg/d. For the previous year she had been taking hydrochlorothiazide 50 mg/d and wax‐matrix KCl 20 mEq/d for hypertension. At surgery a “napkin‐ring” stricture of the midjejunum was found. It had microscopic features consistent with KCl local toxicity. It is speculated that delayed gastrointestinal motility secondary to amitriptyline predisposed this patient to wax‐matrix KCl toxicity and that this potential side effect be considered when prescribing wax‐matrix KCl.
Single Bedtime Dose of Famotidine: Assessment of Its Antisecretory Action by 24‐Hour Intragastric pH Monitoring
Authors: Savarino Vincenzo , Picciotto Antonino , Magnolia Maria Rita , Scalabrini Patrizia , Mela Giuseppe Sandro , Celle Guido
Published: March 2013

The antisecretory efficacy of a single bedtime dose of famotidine, a new potent H2‐receptor antagonist, was evaluated by means of continuous 24‐hour intragastric pH monitoring. Of 20 patients with duodenal ulcers, ten randomly received famotidine 40 mg at 10 PM and ten were monitored without medication for control. Famotidine regimen led to a remarkable reduction of gastric acidity in patients who were treated for duodenal ulcer and the drug‐induced pH levels were significantly different (P < .0001) from those of untreated controls. The antisecretory action lasted for 12 hours, which comprised the nocturnal period, whereas no important difference was found between the two groups for the most part of the daytime. The drug was able to keep intragastric pH above 4 units during almost 50% of the whole 24‐hour period. These results confirm that famotidine is a powerful and long‐acting H2 blocker that relieves gastric acidity during the night and morning hours when administered as a single bedtime dose of 40 mg.
Pharmacologic Effects of A‐49816, a New High‐Ceiling Diuretic
Authors: Luther Robert R. , Ringham Gary L. , Steinberg Frank J. , Patterson Karen J. , Jordan David C. , Rollins Douglas E. , Tolman Keith G.
Published: March 2013

The pharmacologic effects of A‐49816, a high‐ceiling, loop diuretic, were evaluated in a single‐blind, placebo‐controlled, randomized trial. Eighteen (18) normal volunteers aged 19 to 40 years were divided into three groups. The subjects in each group received either placebo or three increasing doses of A‐49816 with at least a one‐week washout between doses. Nine doses of A‐49816 (0.5 to 20 mg) were administered during the entire study. Urine volume and excretion of electrolytes were measured at timed intervals following dosing. A‐49816 increased urine volume and excretion of sodium and chloride. Significant saluresis, chloruresis and diuresis were seen in most time periods following administration of the highest doses (12.5, 15 and 20 mg) of A‐49816. Kaluresis was not consistently seen at any dose. The mean rates of urine output and sodium and chloride excretion were increased relative to placebo within 2 hours of drug administration. The mean rates of urine formation and sodium and chloride excretion peaked at 2–4 hours and often remained elevated at the 6–12 hour interval.
Study of the Action of Cicletanine in Hyperuricemic Patients
Authors: Collinge J. , Roberts C. J. C.
Published: March 2013

The possibility that the drug cicletanine might offer diuresis and reduction in plasma uric acid has been investigated in patients recruited from the rheumatology and general medical clinics. Nine hyperuricemic patients received cicletanine 100 mg daily by mouth for 21 days. Urinary clearance studies and plasma biochemistry were measured twice before treatment, twice at the start of treatment, and twice at the end of the treatment period. No change was observed in the urine volume, absolute or fractional excretion of sodium in response to the drug. There was no measurable change in the plasma uric acid or urinary urate clearance. Creatinine clearance and potassium excretion also remained constant. No adverse effects were observed apart from a possibly drug‐related elevation in serum aspartate amino transferase in one patient. The study provides no support for the postulated diuretic or hypouricemic effects of the drug.
Pharmacokinetics of Cefixime After Once‐a‐Day and Twice‐a‐Day Dosing to Steady State
Authors: Faulkner Robert D. , Bohaychuk Wendy , Desjardins Robert E. , Look Zee M. , Haynes John D. , Weiss Arnold I. , Silber B. Michael
Published: March 2013

The pharmacokinetics of cefixime (CL 284,635; FK027), a new orally active broad‐spectrum cephalosporin, were determined in 26 healthy volunteers, after multiple 200‐mg twice‐a‐day (group 1; N = 13) or 400‐mg once‐a‐day (group 2; N = 13) dosing for 15 days. On study days 1, 8, and 15, mean peak serum concentrations (Cmax) were 1.67, 1.75, and 1.87 μg/mL, respectively, for group 1 and 2.76, 3.04, and 2.67, respectively, for group 2. Over the 15‐day period, mean trough serum concentrations were, on average, 0.40 and 0.08 μg/mL for groups 1 and 2, respectively. Comparison (ANOVA) of serum and urinary excretion pharmacokinetic parameters for cefixime on days 1, 8, and 15 found no significant (P > .05) differences for either group except for a small but significantly (P < .05) earlier time to reach Cmax and higher renal clearance on days 8 and 15 in group 1. These differences, however, are not clinically significant. On study days 1, 8, and 15, mean Cmax and AUC0‐r values for Group 2 were about 1.5 to 2.2 time those for Group 1. Urinary excretion of cefixime accounted for 11.9 to 14.5% and 9.9 to 12.4% of the dose in groups 1 and 2, respectively, over the 15‐day study. Overall, there was no accumulation of cefixime in serum or urine nor was there a reduction in serum concentrations or urinary amounts over the 15‐day dosing period when the drug was given either as a 200‐mg twice‐a‐day or 400‐mg once‐a‐day dosing regimen.
Chloroquine Elimination in Humans: Effect of Low‐Dose Cimetidine
Authors: Ette Ene I. , Brown‐Awala Esther A. , Essien Ettiene E.
Published: March 2013

A controlled study was carried out in ten healthy, male volunteers (randomly distributed into control and test groups of five subjects each) to determine the effect of low‐dose cimetidine on chloroquine elimination. The control group subjects received two tablets of chloroquine sulfate (300‐mg base) only, while the test group subjects took 400‐mg cimetidine at bedtime for four days prior to chloroquine (two tablets of chloroquine sulfate) administration and throughout the duration of the study. Blood samples, 5 mL, were collected periodically after chloroquine administration. The samples were assayed for chloroquine and monodesethylchloroquine using a combination of thin‐layer chromatography and spectrophotometry. Wilcoxon's test for unpaired data at P < .05 was used to determine if there was any significant difference in the elimination of chloroquine in the test group when compared with the control group. The apparent oral clearance rate of chloroquine was reduced from 0.49 ± 0.04 L/d/kg in the control group to 0.23 ± 0.02 L/d/kg in the test group, and the elimination half‐life was prolonged from 3.11 days in the control group to 4.62 days in the test group. There was a 47.04% reduction in the AUC0‐7d of monodesethylchloroquine, the major metabolite of chloroquine, in the test group when compared with the control group. The apparent volume of distribution at steady state was increased from 0.46 ± 0.07 L/kg in the control group to 0.72 ± 0.10 L/kg in the test group. All these changes were statistically significant. The conclusion is that cimetidine impairs the elimination of chloroquine in healthy subjects.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Brain Reward Systems and Abuse Edited by Jorgen Engel et al

Logan's Medical and Scientific Abbreviations Carol ynn M. Logan and M. Katherine Rice, J. B. Lippincott

Senile Dementia of the Alzheimer Type Edited by J. Traber and W. H. Gispin
The Swiss Drug Review and Approval Process
Authors: von Falkenstein R. , Klein P.
Published: March 2013

Several articles have been written1–3 on the Swiss regulatory process, and no attempt is made here to give a more comprehensive description of what to do to obtain approval in Switzerland. Our task is to shed light on the general ways and philosophy behind the Swiss regulations and to report on current developments. Whoever wants to know all the details can consult the rules and guidelines available, a list of which is included in the Appendix.
Bevantolol: A Beta‐1 Adrenoceptor Antagonist with Unique Additional Actions
Authors: Williams E. M. Vaughan
Published: March 2013

Bevantolol is a beta‐1 adrenoceptor antagonist that has been shown to be as effective as other beta blockers for the treatment of angina pectoris and hypertension. Some interesting additional properties, such as the absence of the side effect of cold extremities, required investigation, and a great deal of new evidence has been accumulated during the last three years. This new data is consistent with the proposal put forward a couple of years ago that bevantolol interacts with alpha‐adrenoceptors. All the available evidence, published and unpublished, has been reviewed and fits into a coherent pattern, here arranged into five sections. Chemistry: affinity for alpha‐adrenoceptors. Animal experiments confirm both agonist and antagonist effects on alpha‐receptors, in addition to antagonist activity at beta‐1 receptors. In addition, bevantolol has electrophysiologic effects, including bradycardia by a direct action on the sinus node and a class 1 antiarrhythmic action. Investigations in humans have shown that although bevantolol has a short half‐life, good control of hypertension can be achieved on once‐a‐day dosing. Safety: bevantolol has remarkably few side effects, does not cause cold extremities, and does not significantly affect glomerular filtration rate in patients with renal impairment. Evidence has been obtained in man for interaction with alpha‐adrenoceptors in the brain; and in the peripheral circulation bevantolol does not, as do other beta blockers, increase peripheral vascular resistance, but reduces it. It is suggested that all the additional actions of bevantolol can be attributed to a partial agonist action on alpha‐adrenoceptors.
A Comparison of Enalapril and Metoprolol as Initial Therapy for Mild to Moderate Hypertension
Authors: Nugent Louise W. , Miola Steven R. , Walker J. Findlay
Published: March 2013

The safety and efficacy of step‐one therapy with enalapril, a new angiotensin‐converting enzyme inhibitor, and metoprolol were compared in a double‐blind, multicenter study involving 150 patients who had mild to moderate essential hypertension. After a four‐week period of placebo run‐in, therapy was initiated with twice‐daily administration of either 5 mg of enalapril (N = 75) or 50 mg of metoprolol (N = 75). Patients who did not achieve a supine diastolic blood pressure of less than 90 mm Hg after six weeks of enalapril (maximum dose = 40 mg/d) or metoprolol (maximum dose = 400 mg/d) had hydrochlorothiazide 50 mg/d added to their treatment regimen for an additional six weeks. Both treatments produced significant (P < .001) mean reductions in supine and standing blood pressures after 2, 4, 6, 8, 10, and 12 weeks of active therapy. Maximum reductions from baseline values of supine blood pressure in enalapril‐treated (‐25/‐16 mm Hg) and metoprolol‐treated (‐21/‐15 mm Hg) patients were observed after 12 weeks of single‐ or double‐drug therapy. Approximately two‐thirds of the patients responded to single‐drug therapy; when hydrochlorothiazide was added, response rates increased to 88% of the patients treated with enalapril and 80% of the patients treated with metoprolol. Enalapril produced a consistently greater reduction in systolic blood pressure. Blacks had a significantly smaller mean blood pressure response to both enalapril and metoprolol than did nonblacks. Metoprolol patients had significant mean pulse rate reductions; enalapril patients had no significant change. Four enalapril‐treated and six metoprolol‐treated patients discontinued treatment because of side effects. The results of this study indicate that both enalapril and metoprolol are safe and effective for step‐one therapy in patients with mild to moderate essential hypertension.
Intravenous Pinacidil in the Acute Treatment of Hypertension
Authors: Rijk M. C. M. , Thien Th.
Published: March 2013

Pinacidil (N“‐cyano‐N‐4‐pyridyls‐N′‐1,2,2‐trimethyl‐propyl guanidine, monohydrate), a recently developed direct‐acting vasodilator, was given intravenously in a dosage of 0.1‐0.2 mg/kg body weight to ten untreated hypertensive patients. Pinacidil caused a fall of blood pressure from 170/108 ± 6/3 to 156/80 ± 5/4 mm Hg (mean ± SE). The proportional decrease of mean arterial pressure (MAP) was 13.7 ± 1.6%. Together with the decrease of blood pressure an increase of heart rate by 29.7 ± 6.2% occurred. The heart rate increased by 13.6 beats/min per 10 mm Hg decrease of MAP. Pinacidil also caused significant rise of plasma noradrenaline and plasma renin activity, whereas plasma adrenaline and aldosterone remained unchanged. The serum concentrations of pinacidil and its major metabolite pinacidil‐N‐oxyde were within the expected limits. The authors conclude that intravenously administered pinacidil causes a rapid decrease of blood pressure, but at the cost of a considerable increase of heart rate, and thus does not offer advantages over other vasodilators.
Short‐Term Effects of Beta Blockers Atenolol, Nadolol, Pindolol, and Propranolol on Lipoprotein Metabolism in Normolipemic Subjects
Authors: Harvengt C. , Heller F. R. , Martial Ph. , VAN Nieuwenhuyze Y.
Published: March 2013

The short‐term effect of the blockade of the beta‐adrenergic receptors on serum lipoproteins and the plasma activities of the enzymes involved in the metabolism of the serum lipoproteins: lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT) was evaluated in ten healthy normolipemic and normotensive subjects. In the first part of the study, the first three‐day period of placebo was followed by another three‐day period during which propranolol (120 mg/d) was given. In the second, third, and fourth part of the study, the same schedule was used but pindolol (15 mg/d), nadolol (160 mg/d), atenolol (100 mg/d) were given respectively instead of propranolol. The four drugs induced a significant blockade of the beta‐adrenergic receptors as evaluated by the measurement of the double two‐step test of Master (‐45%). Despite similar blockade, the effect on serum lipid concentrations depended on the type of drug: propranolol induced an increase in triglycerides and apoprotein B‐concentrations and a decrease in serum high density lipoprotein cholesterol (HDL‐C) and apoprotein AI‐concentrations. Pindolol provoked only a slight decrease of serum HDL‐C concentration. Nadolol and atenolol elicited a lowering of the same magnitude in HDL‐C. Except for a possible slight increase in plasma LCAT activity on propranolol, there was no significant change in the plasma activities of LPL, HL, and LCAT during the blockade of the beta‐adrenergic receptors with the drugs used. It is difficult to draw firm conclusions in regard to the mechanism by which beta blockers given to patients for much longer periods of time alter lipoprotein metabolism from results obtained in normolipemic subjects receiving beta blockers for only three days. It seems that pindolol modifies the serum lipoprotein pattern less likely than propranolol, nadolol, or atenolol. This difference could be attributed to the intrinsic sympathomimetic activity of pindolol of which the other beta blocking drugs that were used are devoid. The mechanism by which the serum lipid changes can be induced by beta blockade does not involve a lower activity of any of the plasma enzymes regulating the intravascular metabolism of lipoproteins.
Comparative Efficacy of Pirmenol and Procainamide in a Drug‐Resistant Population with Ventricular Tachycardia
Authors: Miura Dennis S. , Schwartz Joseph , Laux Barbara , Wynn Jonathan , Keefe Deborah , Somberg John C.
Published: March 2013

The acute antiarrhythmic properties of pirmenol were studied in 12 patients who failed clinical oral drug therapy with a history of a cardiac arrest or sustained ventricular tachycardia (VT). Programmed electrical stimulation studies were performed in ten men and two women with a mean age of 63 ±2 years. All patients had inducible ventricular tachycardia by programmed electrical stimulation when they were off all antiarrhythmic therapy. Patients were then tested on procainamide, 1000 mg, administered intravenously, and ventricular tachycardia could be provoked in nine of twelve patients. Pirmenol was given intravenously, 1.1 mg/kg bolus followed by 40 μg/kg/min over 40 minutes prior to drug testing. Pirmenol did not significantly change the baseline heart rate, blood pressure, or measured electrocardiographic values from control values. Ten of 12 patients were still inducible to ventricular tachycardia on pirmenol. Procainamide protected one of nine patients against VT induction. In patients still inducible on drug therapy, the VT rate was significantly slowed from 221 beats/min to 166 beats/min on pirmenol and to 200 beats/min on procainamide. The effects of this new antiarrhythmic agent were similar to procainamide in this drug‐resistant study population.
The Effect of Dietary Fiber on the Bioavailability of Digoxin in Capsules
Authors: Johnson Brian F. , Rodin Steven M. , Hoch Kathleen , Shekar Vasantha
Published: March 2013

Sixteen healthy volunteers were regularly given 0.4 mg of digoxin daily as two capsules with breakfast. After ten days during which breakfast was supplemented with 11 g of bran fiber, steady‐state predose mean serum digoxin was lower (0.89 ± 0.19 versus 0.84 ± 0.18 ng/mL, P< .05) and mean 24‐hour area under curve determination was lower (30.5 ± 6.1 versus 28.4 ± 6.0 ng ṁ hr/mL, P< .05) than during the control period without bran. Height and time of peak serum digoxin, and 24‐hour urinary digoxin were not significantly different. The 6 to 7% reduction in digoxin absorption from capsules is less than that reported from tablets and is probably clinically unimportant.
The Novel Therapeutic Implications of Azlocillin's Dose‐Dependent Pharmacokinetics: Contributing Physiologic Mechanisms and a Prospective, Cross‐Over Designed Trial
Authors: Whelton Andrew , Stout Robert L. , Spilman Patricia S. , Delgado Fernando A. , Watson Alan J.
Published: March 2013

Azlocillin is an important acylureido penicillin antibiotic for the management of complex gram‐negative infections particularly those caused by Pseudomonas species. The current studies demonstrate that it manifests dose‐dependent pharmacokinetics during the usual regimens of clinical dosing, that enterohepatic recirculation does not occur and that renal tubular secretion (maximum renal tubular secretory capacity 300 ± 30 μg/min) and hepatic metabolism appear to be the dominant contributors to the dose‐dependent nature of azlocillin. The possible therapeutic implications of azlocillin's dose dependency were evaluated by undertaking a six‐day randomized, prospective, cross‐over design study to evaluate the pharmacokinetic disposition of the drug during a 3‐g q4h (typically used in adults) regimen versus a 5‐g q8h regimen. By using the area under the serum‐time concentration curve (AUC) as the major comparative parameter for these two regimens, the results demonstrate that both regimens provide approximately equal quantitative amounts of the drug systemically as a result of azlocillin's dose dependency. The AUC values, although not therapeutic end points, nonetheless correlate well with clinical response to antibiotic therapy. The 5‐g q8h regimen was well tolerated. It is less disruptive for patients, requires half the number of intravenous administrations, 17% less drug, and is more cost effective than the 3‐g q4h regimen.
Chloroquine in Human Milk
Authors: Ette Ene I. , Essien Ettiene E. , Ogonor James I. , Brown‐Awala Esther A.
Published: March 2013

Simultaneous milk and saliva samples were collected over a seven‐day period from five lactating subjects after they had ingested two tablets of chloroquine sulfate (300 mg base). The samples were analyzed for chloroquine content by use of a combination of thin‐layer chromatography and spectrophotometry. Regression analysis of two variables subject to error was used to determine the milk:saliva levels relationship. The Student's t test for paired data at .05 level of significance was used to evaluate the relationship between chloroquine levels in milk and saliva. The milk:saliva chloroquine concentrations ratio obtained by regression analysis was 0.89 ± 0.08 (r = .93; P < .05), and this compared favorably with the value of 0.99 ± 0.07 obtained from the ratio of the AUC. There were no significant differences in the Tmax, Cmax, AUC, clearance, and elimination half‐life values of chloroquine in milk and saliva (P > .05). Milk and saliva appear to be part of the central compartment. The amount of chloroquine estimated to be consumed by a nursling over a 24‐hour period is about 0.55% of a 300‐mg dose consumed by the mother. The data suggest that milk chloroquine levels can be estimated from saliva levels.
Renal Tolerance of Rubidium Chloride: Short‐Term Clinical Evaluation
Authors: Tuoni Mario , Marchitiello Maria , Paternoster Giuseppe , Gerace Silvana , Palla Roberto , Placidi G. Franco , Lenzi Alessandro , Toschi Daniela , Meltzer Herbert L.
Published: March 2013

The rubidium and lithium ions are known to have opposite effects on a wide range of biochemical and behavioral parameters in experimental animals. Based on the proven effectiveness of lithium as an antimanic agent, several trials have been conducted with rubidium in the acute treatment of the depressive phase of bipolar illness. The results to date are promising. However, the 30‐ to 60‐day biologic half‐life of rubidium has mandated careful studies of potential toxicity before engaging in long‐term administration of this ion to depressive subjects. One area of potential concern is the possibility of renal toxicity, which could be expressed as unexpectedly increased retention of rubidium. The data in this paper show that after 15 days of rubidium administration, there are no changes beyond the normal range in a variety of kidney function tests, including in four enzymes which are specific markers of tubule cell function.
Alprazolam: Effects on Sleep and Withdrawal Phenomena
Authors: Kales Anthony , Bixler Edward O. , Vela‐Bueno Antonio , Soldatos Constantin R. , Manfredi Rocco L.
Published: March 2013

Alprazolam was evaluated in chronic insomniacs in a 1‐mg bedtime dose. The 16‐night sleep laboratory protocol included four placebo‐baseline nights followed by seven nights of drug administration and five placebo‐withdrawal nights. On the first three drug nights (nights 5 to 7), the drug was highly effective in inducing and maintaining sleep with this short‐term use. By the end of the one week of administration (nights 9 to 11), however, the drug had lost about 40% of its efficacy. During drug use, one subject reported some difficulty in controlling expression of inappropriate emotions when interacting with others, which suggested the presence of disinhibition. On the third night following drug termination, there was a significant increase in sleep difficulty above baseline levels (rebound insomnia). This worsening was of comparable magnitude to the peak improvement of sleep with drug administration. Thus, the clinical utility of alprazolam when administered to insomniac patients appears to be limited because of a relatively rapid development of tolerance and possible disinhibitory reactions during drug use and the occurrence of rebound insomnia following withdrawal.
Pharmacokinetics of Low‐Dose Intravenous Pethidine in Patients with Renal Dysfunction
Authors: Chan K. , Tse J. , Jennings F. , Orme M. L'E.
Published: March 2013

The kinetics and elimination of pethidine (meperidine) after intravenous administration (150 μg/kg) to ten healthy volunteer subjects were compared with those obtained from 18 patients who suffered from varying degrees of renal dysfunction. In both groups of subjects, pethidine was eliminated triexponentially from plasma. However, plasma concentrations in the patients (who were subdivided into patients with severe dysfunction, moderate dysfunction, and mild dysfunction) were consistently higher. The mean ± SEM elimination half‐life (t1/2) of pethidine was significantly longer in the three groups of renal patients: 7.9 ± 1.1, 20.2 ± 13.6, 16.6 ± 5.4, and 14.3 ± 3.1 hr, respectively, for healthy volunteers, patients with severe, moderate, and mild dysfunction; their mean ± SEM creatinine clearances were 97.3 ± 7.5, <9.5, 30.0 (3.7), and 63.3 ± 8.5 mL/min respectively. The mean plasma clearance of the drug was higher in healthy subjects (342.7 ± 62.5 mL/min) than various groups of renal patients (99.9 ± 11.6, 120.9 ± 45.8, and 123.8 ± 34.1, respectively, for patients with severe, moderate, and mild dysfunction). Impairment of renal function also reduced total plasma protein binding: 58.2 ± 5.0% in healthy subjects and 31.8 ± 3.9%, 44.5 ± 5.0%, and 42.5 ± 5.6%, respectively, for the three renal patient groups. The percentage of pethidine recovered in the urine was significantly lower in the severe dysfunction group while norpethidine recovery was significantly lower in all three groups of renal patients. These observations suggested that the longer elimination t1/2 of pethidine in renal patients may be attributable to a more extensive distribution of pethidine in the body (with a decrease in plasma protein binding) and a lower plasma clearance of the drugs.
The Effects of a Beta‐2 Selective Adrenergic Agonist and a Beta‐Nonselective Antagonist on Theophylline Clearance
Authors: Lombardi Thomas P. , Bertino Joseph S. , Goldberg Arnon , Middleton Elliott , Slaughter Richard L.
Published: March 2013

Beta‐adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 ± 12.9 vs 40.6 ± 9.9 mL/min/1.73m2; P < .01) increased half‐life (8.37 ± 1.77 vs 12.32 ± 2.70 hours; P < .05), and increased postinfusion theophylline concentration (13.5 ± 2.7 vs 18.95 ± 2.5 μg/mL; P < .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 ± 13.0 vs 75.0 ± 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 ± 12.7 vs 36.1 ± 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta‐2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta‐adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.