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Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight-based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment.

Oncology is the frontline of drug development. The current pharmaceutical pipeline is disproportional focused on oncology, where about 1/3 of all phases of development is in this therapeutic area. The emphasis brings about substantial breakthroughs and has made positive impact on the quality of life. However, oncology remains a threat to human existence. To facilitate this process, a comprehensive list of novel/first molecularly targeted oncology drug approvals by the FDA from 2017 to 2020 is assessed. Here, we focus on molecularly targeted oncology drugs and not cytotoxic ones, although the latter remain important. To achieve this purpose, besides their sponsors, years of approval, drug classes, and cancer indications, clinical significance is included. The results show that approved molecularly targeted drugs span across diverse classes, including small molecule receptor inhibitors, and biologics such as monoclonal antibodies, antibody-drug conjugates, check-point inhibitors (i.e., PD1, PDL1, CTLA4) and CAR-T cell therapies. Although complete cure of cancer remains limited, we have made substantial inroads and more is yet to come. Moreover, many of these new knowledge can be extrapolated to other therapeutic areas, especially to those of currently unmet medical needs such as in neurology and other chronic diseases.

Von Willebrand Disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding symptoms. Patients with VWD can experience easy bruising, epistaxis, gastrointestinal and oral cavity bleeding, as well as heavy menstrual bleeding and bleeding after dental work, surgical procedures, and childbirth. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cut-off values of VWF:Ag and platelet-dependent VWF activity assays in the diagnosis of VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. Two investigators screened and abstracted data. Risk of bias was assessed using QUADAS-2 and certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity and reported patient important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis, including the approach to patients with VWF levels that have normalized with age (6 studies), VWF cut-off levels for the diagnosis of Type 1 VWD (9 studies), and platelet-dependent VWF activity/VWF:Ag ratio cut-off levels for the diagnosis of Type 2 VWD (6 studies). The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD versus simply removing the disease in patients with VWF levels that have normalized with age. For the diagnosis of Type 1 VWD, in patients with VWF:Ag

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges. Objective: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. Methods: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment. Results: The panel agreed on 11 recommendations. Conclusions: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.

Background Treatment of postprandial hyperglycemia could be needed when basal insulin added to oral therapy does not maintain glycated haemoglobin (HbA1C) targets in type 2 diabetes mellitus. Knowing individual and regional patterns of postprandial hyperglycemia in this setting might improve therapeutic decisions. Methods Patient-level self-monitored blood glucose data were pooled from six studies of insulin glargine for patients with HbA1C ≥ 7.0% after 24 weeks. Percentages of participants with highest daily postprandial blood glucose and greatest postprandial increments after each of the three daily meals were calculated and compared between four geographical regions; USA, Canada, Germany, and other European countries. Results For 494 participants (mean age 60.1 years, diabetes duration 9.6 years, and BMI 29.8 kg/m2), mean endpoint HbA1C was 7.8%. On insulin glargine treatment, highest postprandial blood glucose most often occurred post-dinner (44% of participants) and greatest postprandial increments post-breakfast (46% of participants) in all regions. Participants with greatest postprandial increments post-breakfast were older and experienced less HbA1C improvement with insulin glargine than those with greatest postprandial increments after other meals. Post-breakfast and post-dinner postprandial blood glucose was higher in the USA and Canada versus Germany, and in the USA versus Other European countries (all p

Aim To assess patient-reported outcomes associated with initiating insulin glargine among insulin-naive patients with type 2 diabetes mellitus (T2DM). Methods This was a pooled analysis of patient-level data from Phase 3, randomized controlled trials evaluating once-daily insulin glargine vs. comparator treatment for ≥24 weeks in previously insulin-naive adult patients with T2DM and poor glycaemic control. Eligible studies utilized strict, predefined insulin titration algorithms with weekly dose-adjustment to achieve fasting plasma glucose (FPG) levels of ≤5.6 mmol/l. Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) change (c) and status (s) versions. Results A total of 1577 patients from four studies were included; 830 patients treated with insulin glargine and 747 with comparators. At week 24, DTSQc scores improved in both groups with a significantly higher increase in treatment satisfaction for insulin glargine vs. comparators (13.5 vs. 12.1; p

Background Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline. Methods This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] > target), algorithm 2 (2 IU increase every 3 days, if FPG > target), or algorithm 3 (treat-to-target, generally 2–8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms. Results Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P

Investigate contributors to treatment satisfaction in type 1 diabetes (T1D).Post-hoc analysis using the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) in 771 T1D patients from two 28-week trials comparing once-daily insulin glargine 100U/mL (Gla-100) with once- or twice-daily NPH neutral protamine Hagedorn (NPH) insulin.Gla-100 was associated with a significant improvement in treatment satisfaction versus NPH (overall population adjusted mean [standard error] DTSQs change from baseline: +1.13 [0.30] versus -0.04 [0.31]; p=0.006). In the overall population, treatment satisfaction improvement with all insulin regimens was related to less frequent severe hypoglycemia (coefficient-0.077; p=0.040) and HbA1c reduction (-0.066; p=0.082). By treatment regimen, relationships between treatment satisfaction and these outcomes approached or attained statistical significance for NPH insulin, but not Gla-100. In the overall population, predictors of treatment satisfaction improvement included: Gla-100 treatment (estimate 1.17, p=0.006), lower baseline DTSQs (-0.57, p0.001), study (-1.01, p=0.019), lower severe hypoglycemia rate (0.17, p=0.012), and higher baseline HbA1c (0.44, p=0.014). By treatment regimen, these predictors remained significant for NPH insulin.Gla-100 resulted in a significant improvement in treatment satisfaction versus NPH insulin, independent of baseline disease characteristics and clinical outcomes.

This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50 of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.

Novel approaches to drug development along with incentives to reward risk undertaken during early drug development have been proposed to improve the medical product development process. The American College of Clinical Pharmacology held its 19th Frontiers Symposium in mid-2007 to provide a forum to share new knowledge about disease progression models and adaptive and other novel trial designs. These topics reflect the changing paradigm of drug development and regulatory innovation as outlined in the Food and Drug Administration's Critical Path Initiative. This meeting report summarizes some of the presentations and panel discussions among academic, industrial, and regulatory participants regarding clinical trial design, including adaptive Bayesian approaches.

Objective: This study evaluated the effect of advanced age on the single-dose and steady-state pharmacokinetics of the angiotensin converting enzyme inhibitor fosinopril along with the diuretic hydrochlorothiazide. Design and Setting: Open-label, multiple-dose study in a hospital-based clinical study unit. Study Participants: Twelve young (21 to 30 years) and 12 elderly (66 to 75 years) healthy men. Interventions: Participants received a combination tablet of fosinopril 20mg and hydrochlorothiazide (HCTZ) 12.5mg as a single daily dose for a total of 6 doses. Drug concentrations were measured on days 1 and 7 by radioimmunoassay (fosinoprilat, the active diacid) and by HPLC (HCTZ) for calculation of first-dose and steady-state pharmacokinetic parameters. Results: Fosinoprilat steady-state maximum serum concentration (Cmax) was somewhat higher in the elderly, but area under the serum concentration-time curve (AUC) and other pharmacokinetic parameters were similar in the young and elderly adults. As expected with age-related diminished renal function, HCTZ clearance was lower in the elderly, while its cumulative urinary excretion was similar in the two groups. Conclusion: Advanced age is not accompanied by a clinically meaningful change in the pharmacokinetic profiles of fosinopril and HCTZ and does not warrant dose adjustment based on advanced age alone. The favourable pharmacokinetic feature of fosinopril of having dual (renal and hepatic) and compensatory elimination pathways is preserved in the elderly during combination therapy with HCTZ.

Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant.

Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline.This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] target), algorithm 2 (2 IU increase every 3 days, if FPG target), or algorithm 3 (treat-to-target, generally 2-8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms.Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P 0.0001, respectively), though results were not significantly different when adjusted for reductions in HbA1c (0.36 IU/kg, 0.43 IU/kg, and 0.31 IU/kg for algorithms 1, 2, and 3, respectively). Yearly hypoglycemic event rates (confirmed blood glucose56 mg/dL) were higher for algorithm 3 than algorithms 1 (P = 0.0003) and 2 (P 0.0001).Three algorithms for initiation and titration of insulin glargine in patients with T2DM resulted in similar levels of glycemic control, with lower rates of hypoglycemia for patients treated using simpler algorithms 1 and 2.

Financial instruments, such as professional membership fees, are part of the science and technology policy toolkit for creating an environment conducive to developing an international health knowledge network. To minimize a hurdle to global knowledge exchange in clinical pharmacology, the American College of Clinical Pharmacology reevaluated fees for its international members. Secondary market research was conducted on salary data available from US-based multinational firms. Salary comparisons for the same position based in the United States and in a developing economy were used to generate an index ratio. Applying this ratio, a tiered-membership fee structure was constructed for the approximately 120 countries where gross national income meets the World Bank classification of "developing economy." The index ratio serves as a paradigm for structuring fees across a variety of programs. With the implementation of an adjusted dues structure, information and networks of colleagues are now more accessible to clinical pharmacologists in developing economies.

Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization-collisionally activated dissociation tandem mass spectrometry (PCI-CAD MS/MS). After juice administration, PCI-CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.

The antiviral drug zidovudine (ZDV) and the analgesic and antipyretic agent acetaminophen (AP) are both biotransformed in the liver of humans to ether glucuronides. A previous clinical trial of ZDV suggested the potential for a clinically significant interaction between AP and ZDV, probably based upon competing hepatic metabolism. To study the mechanism of this potential competition between AP and ZDV as substrates for uridine diphosphoglucuronyltransferase (UDPGT), enzyme kinetic studies were performed using rat liver microsome preparations. Cross inhibition studies demonstrated that AP glucuronidation was competitively inhibited by ZDV, while ZDV glucuronidation was slightly inhibiced by AP in a noncompetitive interaction.

Twenty-four healthy volunteers aged 22 to 78 years received 650-mg doses of acetaminophen (AAP) on five separate occasions. The modes of administration were: intravenous AAP by 5-minute infusion; oral AAP as two 325-mg tablets in the fasting state; oral AAP 650 mg as an elixir preparation in the fasting state; tablets with food; and elixir with food. Plasma concentrations of AAP were determined by high-pressure liquid chromatography for up to 12 hours after the dose. In both the young and the elderly groups, the four oral modes of administration were significantly different with respect to peak plasma concentration (P less than 0.001), time to peak plasma concentration (P less than 0.001), and systemic availability (P less than 0.01). Although food slowed the rate of absorption of both oral preparations, no significant difference in peak acetaminophen plasma concentration or time of peak concentration was observed as a function of age. Absolute systemic availability of elixir and tablets in the fasting state tended to be lower in the elderly subjects (P less than 0.05). However, when either preparation was coadministered with food, there were no differences between the two age groups. Thus, age as such does not appear to be a critical determinant in the design of oral acetaminophen dosage schedules.

Synopsis: Lorazepam1 is a 3- hydroxy- 1,4- benzodiazepine derivative in clinical use as a sedative, antianxiety and hypnotic agent. The 3-hydroxy configuration of lorazepam results in pharmacokinetic properties similar to those of oxazepam and temazepam. Unlike diazepam, lorazepam is not transformed into active metabolic products and has a relatively short half-life. However, because of differences in the lipophilicity and extent of tissue distribution, intravenous lorazepam has a slower onset of action and appears to have a longer duration of action than single doses of diazepam. Controlled therapeutic trials have shown lorazepam to be more effective than placebo as a hypnotic, in treatment of acute and chronic anxiety, in anxiety associated with functional or organic diseases and for surgical premedication. When lorazepam and diazepam have been compared at a dosage ratio of 1: 5, most studies have reported similar efficacy and tolerability. The most commonly reported side effects are dose-related consequences of central nervous system depression. Local complications following intravenous injection of lorazepam appear to occur less frequently than with diazepam. Pharmacokinetics: Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative in clinical use as a sedative, antianxiety, and hypnotic agent. The 3-hydroxy configuration of lorazepam renders it similar in its pharmacokinetic properties to oxazepam and temazepam. The major metabolic pathway of lorazepam in humans involves direct conjugation to glucuronic acid, yielding a water-soluble glucuronide metabolite. As such, the metabolic profile of lorazepam is straightforward, and does not involve transformation into active metabolic intermediates as is the case with benzodiazepines such as diazepam and chlordiazepoxide. Because glucuronide conjugation in humans proceeds at a faster rate than does oxidation, the half-life of lorazepam is considerably shorter than that of benzodiazepines such as diazepam. Furthermore, it appears that factors such as old age and hepatocellular disease have less effect on the disposition of lorazepam than on the pharmacokinetics of benzodiazepines such as diazepam that are transformed by oxidative mechanisms. Because the lipophilicity of lorazepam is much less than that of the prototype benzodiazepine, diazepam, the onset of clinical activity of intravenous lorazepam following a single dose is much slower than that of diazepam. This effect can be attributed to the slower rate of lorazepam’s passage across the blood brain barrier. Since the extent of tissue distribution of lorazepam also is less than that of diazepam, single doses of lorazepam will appear to have a longer duration of action than will single doses of diazepam. The pharmacodynamic profile of lorazepam in contrast to that of diazepam thus appears ‘paradoxical’ when one compares the difference in their elimination half-life. Physiological Effects: Lorazepam rapidly penetrates the central nervous system (CNS) after intravenous administration and produces dose-dependent CNS depression. Consequently, lorazepam at dosages of 1 mg or more causes sedation, impairment of psychomotor performance and visual function, and produces anterograde, but not retrograde, amnesia. Effects of usual therapeutic dosages have minimal effects on cardiovascular or on respiratory function in healthy subjects. Lorazepam may produce mild respiratory depression in patients with pulmonary disease. Therapeutic Studies: The principal uses of lorazepam in clinical practice include its administration as a sedative or sleep-inducing agent, and as an antianxiety agent for ambulatory and hospitalised individuals. Lorazepam also finds considerable use as a premedicant drug prior to surgical procedures. Lorazepam is an effective sleep-inducing or hypnotic agent in usual therapeutic doses of 2 to 4mg at bedtime. Both clinical efficacy and the occurrence of unwanted morning ‘hangover’ effects are related to dose, and clinicians must weigh the more predictable efficacy of higher doses against the greater likelihood of morning hangover. Parenteral lorazepam also has been used to maintain a state of sedation and muscle relaxation in patients undergoing assisted ventilation. Acute episodes of severe anxiety or panic also are effectively treated by lorazepam, particularly by the parenteral route. The most widespread use of lorazepam is in the treatment of ambulatory individuals with neurotic anxiety. The usual range of effective doses is 2 to 6mg per day, in divided doses. The majority of controlled clinical trials involving this disorder last 3 to 4 weeks; understanding of lorazepam’s benefits and potential hazards for periods longer than 10 weeks is lacking. Numerous controlled trials clearly demonstrate that lorazepam is more effective than placebo in the treatment of anxiety. When compared with diazepam, at a dosage ratio of 1: 5 the majority of controlled trials indicate that lorazepam and diazepam are approximately equivalent in efficacy. Furthermore, the incidence of unwanted side effects (primarily drowsiness and oversedation) with both drugs is similar, and appears to be dose-dependent. A few of the studies suggest that lorazepam has greater efficacy and possibly less unwanted toxicity than diazepam, but this is not a consistent finding. Lorazepam has been extensively evaluated in the treatment of anxiety associated with functional or organic medical diseases. Again, lorazepam is clearly superior to placebo in such disorders. However, its efficacy is largely confined to improvement of the anxiety component of the disease process. Lorazepam should not be expected to produce improvement as such in the natural course of medical disease, such as hypertension, ischaemic cardiovascular disease, or peptic ulcer disease. Lorazepam also finds considerable use as a premedicant prior to diagnostic or surgical procedures. The anterograde antirecall properties of lorazepam are particularly useful in this context. The sedative, anxiolytic and amnesic effects of lorazepam when used as a premedicant are dose-dependent, and probably are of faster onset following parenteral as opposed to oral doses. The duration of lorazepam’s action after single doses may be considerably longer than that of comparable doses of diazepam. This property of lorazepam may be advantageous in some circumstances, but may also be a disadvantage when residual effects of premedicant administration are undesirable. An advantage of lorazepam, however, is that local complications following intravenous administration appear to be considerably less frequent than those associated with diazepam. Lorazepam does have properties that render it a useful addition to the existing group of benzodiazepine derivatives. However, the availability of lorazepam should not be construed as a remarkable ‘breakthrough’ in the treatment of anxiety. Side Effects: Adverse effects of lorazepam are largely comprised of predictable consequences of dose-dependent central nervous system depression. The most commonly reported adverse effects are drowsiness, oversedation, weakness, impaired coordination, and sometimes disorientation and confusion. These effects are almost always reversible upon reduction of dose. Reported drug interactions with lorazepam are rare, but more well controlled pharmacokinetic studies are needed of drug interactions with lorazepam. Data available to date suggest that the disposition of lorazepam in humans is minimally altered by old age or by the presence of renal or hepatic disease. There are relatively few reports of lorazepam overdosage. However, the findings suggest that, as in the case of other benzodiazepines, serious poisoning due to lorazepam alone is very unusual.

This paper describes a new high-pressure liquid chromatographic method used for quantitation of bumetanide in urine and plasma. Compared to previously reported methods, this assay offers the advantages of increased sensitivity, shortened sample preparation time and decreased instrumentation requirements. After addition of the 4-benzyl derivative of bumetanide as the internal standard, both urine and plasma underwent a single extraction with ethyl acetate at an acidic pH. The organic extract was separated, evaporated to dryness, reconstituted with methanol, and chromatographed using a reversed-phase C-18 radial compression cartridge with fluorescence detection. Sensitivity limits are approximately 1 ng of bumetanide per mL of plasma, with a coefficient of variation for identical samples never exceeding 6%. The method lends itself to pharmacokinetic and pharmacodynamic studies of bumetanide in humans following single therapeutic doses.

Eighteen healthy volunteers received single 650-mg doses of acetaminophen by 5-min intravenous infusion, in tablet form by mouth in the fasting state, and in elixir form orally in the fasting state in a three-way crossover study. An additional eight subjects received two 325-mg tablets from two commercial vendors in a randomized crossover fashion. Concentrations of acetaminophen in multiple plasma samples collected during the 12-hr period after each dose were determined by high-performance liquid chromatography. Following a lag time averaging 3-4 min, absorption of oral acetaminophen was first order, with apparent absorption half-life values averaging 8.4 (elixir) and 11.4 (tablet) min. The mean time-to-peak concentration was significantly longer after tablet (0.75 hr) than after elixir (0.48 hr) administration. Peak plasma concentrations and elimination half-lives were similar following both preparations. Absolute systemic availability of the elixir (87%) was significantly greater than for the tablets (79%). Two commercially available tablet formulations did not differ significantly in peak plasma concentrations, time-to-peak, or total area under the plasma concentration curve and therefore were judged to be bioequivalent.

This study compared the systemic absorption of topically administered lidocaine in elderly and young adult patients who were undergoing fiberoptic bronchoscopy. Fourteen elderly subjects aged 60-72 years (mean 67 years) and five young subjects age 31-48 years (mean 42 years) were compared with respect to dosage requirements to achieve satisfactory local anesthesia, rate and extent of lidocaine systemic absorption, plasma drug levels, elimination half-life, and drug side effects. Blood samples were drawn prior to, during, and for an average of 3 hours after the completion of bronchoscopy. Lidocaine plasma concentrations averaged in the range of 3.04-0.88 micrograms/ml from the beginning of the procedure to the end of blood sampling. Despite high cumulative amounts of 19 mg/kg (1200 mg) of lidocaine administered topically, the regimen proved relatively safe and achieved satisfactory anesthesia. In patients without known risk factors either for delayed hepatic lidocaine clearance or for enhanced mucosal absorption, the regimen is suitable for both young and old individuals.

The chemistry, pharmacology, uses, side effects, pharmacokinetics and dosage of butorphanol tartrate, a narcotic analgesic with antagonist properties, are reviewed. When administered intramuscularly or intravenously, butorphanol tartrate appears to be as effective for relieving moderate to severe pain as are pentazocine, meperidine and morphine. Butorphanol produces sedation more commonly and, at therapeutic dosages, depresses respiration as much as these other narcotic analgesics. A limited number of long-term clinical studies suggest a lower physical dependence liability with butorphanol than with other narcotic analgesics. Butorphanol is more expensive than morphine and, for most patients, offers no significant advantages over morphine for short-term use. Because butorphanol's cardiovascular effects are not completely understood, morphine also remains the drug of choice for pain associated with myocardial infarction.

Thirty-two healthy men and women, 23 to 78 yr old, received single 650-mg intravenous doses of acetaminophen and the drug's kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half-life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetics data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary.

The development and implementation of a two-month inservice training program for hospital pharmacy supportive personnel is discussed. A task-oriented approach was used to define the instructional objectives of the program. To emphasize the job-related nature of the instruction, conferences and workshops were selected as the primary teaching methods. A specific instructional plan was designed for drug conferences, giving the trainee an active role in the learning of drug names and dosage forms. On-the-job experience, comprising 30% of the training time, gradually was incorporated into the program. Staff pharmacists and supervisors assumed the teaching responsibilities. During weekly evaluation sessions with each trainee, the coodinator discussed the trainee's performance, pin-pointed deficiencies and suggested means of improvement. The benefits of the program, in terms of selection and sequence of instructional programs, student assessment and program evaluation, are discussed.

Local anesthetic agents are topically applied during diagnostic procedures such as bronchoscopy. These routine procedures are associated with only rare reports of drug toxicity or extensive systemic drug absorption. We report a case of rapid systemic absorption and elevated plasma lidocaine concentrations following a fiberoptic bronchoscopy procedure in a man with oral candidiasis and lung cancer.

Twenty-eight healthy volunteers (age range, 22-78 years) received 650 mg of acetaminophen (AAP) on three separate occasions. The modes of administration were 1) intravenous, 5-minute infusion; 2) oral, with two 325-mg tablets; and 3) oral, with 650 mg as an elixir preparation. Plasma levels of AAP were determined in blood samples drawn up to 12 hours after the dose. The mean (+/- sd) kinetic variables for absorption of AAP from tablets in young and elderly were peak plasma concentration, 11.8 (+/- 4.2) vs 10.9 (+/- 4.1) micrograms/ml; peak time, 0.79 (+/- .54) vs 0.69 (+/- .40) hours after the dose; absorption half-life, 12.6 (+/- 9.8) vs. 8.2 (+/- 5.3) minutes; and absolute systemic availability, 79 (+/- 9) vs 72 (+/- 11) per cent. For AAP elixir, the corresponding values were 12.6 (+/- 5.4) vs 13.7 (+/- 6.0) micrograms/ml; 0.52 (+/- .24) vs 0.54 (+/- .51) hours; 8.6 (+/- 6.2) vs 6.1 (+/- 6.6) minutes; and 87 (+/- 9) vs 80 (+/- 9) per cent. Absolute bioavailability of both oral dosage forms was significantly less then 100 per cent in all groups. Elderly subjects tended to show lower availability of both oral preparations, but the difference was of borderline significance (P less than .50). Age did not influence any other measures of absorption. Since the absorption rate of acetaminophen may be indicative of the gastric emptying rate, age does not appear to alter this rate-limiting step in drug absorption.

Stress thallium imaging with intravenous dipyridamole permits assessment of coronary artery disease (CAD) without the need for exercise. However, intravenous dipyridamole is available in the United States only on an experimental basis. To study the use of oral dipyridamole as a clinically available alternative to intravenous dipyridamole for this purpose, 100 patients underwent thallium imaging with oral dipyridamole. Each patient received 300 mg of pulverized tablets in a 30-ml suspension. Maximal increase in mean heart rate and decrease in mean blood pressure occurred 30 minutes after ingestion. At 45 minutes, 2 mCi of thallium was given intravenously and serial imaging was begun within 7 minutes. The serum dipyridamole level (mean ± standard deviation) 45 minutes after 300 mg was administered orally (3.7 ± 2.2 μg/ml) was similar to that 5 minutes after 0.56 mg/kg was given intravenously (4.6 ± 1.3 μg/ml). Fifty-five patients had some adverse effects between 15 and 75 minutes after oral ingestion, including nausea, headache, dizziness, chest pain (25 patients) and electrocardiographic changes (14 patients). Intravenous aminophylline was used to resolve these adverse effects in 21 patients. There were no severe arrhythmias, myocardial infarctions or deaths. Of the 43 patients with angiographically documented CAD, 39 had an initial perfusion defect that redistributed on the delayed images. When the results in patients who had undergone catheterization were analyzed by individual segment, the presence of thallium redistribution was associated with normal or hypokinetic contrast left ventriculographic wall motion of that segment, whereas the presence of a persistent defect was associated with akinesia or dyskinesia (Fisher's standardized Z = 9.14). In conclusion, stress thallium imaging without exercise is feasible with a clinically available form of dipyridamole—the oral suspension. It is safe and may be used for evaluation of CAD to unmask regions of hypoperfused viable myocardium.

Rifampin can be associated with severe adverse effects such as hepatitis, acute renal failure, hemolytic anemia, and thrombocytopenia. Thrombocytopenia has traditionally been associated with intermittent therapy. This article reports the occurrence of rifampin-associated thrombocytopenia in an indigent patient after a four-month lapse in therapy for pulmonary tuberculosis. The patient's platelet count dropped rapidly to a level of 1000/mm3 after receiving a single 600 mg dose of rifampin. After returning to a normal level of > 100 000/mm3, the patient's platelets again dropped to 1200/mm3 with readministration of rifampin. The long-term therapy necessary to eradicate the Mycobacterium tuberculosis organism makes economic considerations important. This patient and other indigent patients who may be poor compliers because they are unable to buy the necessary medication may be at a higher risk for adverse reactions.

Renal and hemodynamic responses to bumetanide in hypertension: Effects of nitrendipine. The effects of a calcium antagonist on the response to a loop diuretic were tested in eight hypertensive patients while they received 120mmol · 24hr-1 of dietary Na. Nitrendipine (N; 20 mg) or placebo (P) was administered twice daily for five days and bumetanide (B; 1 mg, i.v.) for the last three days of each period. Cardiac index (CI) was measured during tilt. B alone significantly (P < 0.05; N = 7) reduced CI and increased total peripheral resistance; N prevented these effects of B. Neither drug altered BP consistently. Although three days of B increased plasma renin activity (PRA) during P and N, it increased plasma aldosterone (PAldo) only during P (P, 4.4 ± 1.3 to 7.6 ± 1.0; P < 0.05. N, 5.7 ± 1.3 to 6.0 ± 1.3; pg · liter-1; NS). B increased Na excretion without changing GFR or RPF; this was followed by 18 hours of decreased renal Na excretion. These actions were unchanged by N. N did not change the cumulative excretion of B (P, 268 ± 35 vs. N, 217 ± 21 µg) or the relationship between Na excretion and the log of B excretion. However, Na excretion was increased (P < 0.05) by 40 to 60% in the six hour period following the first two doses of N. Therefore, the cumulative Na balance was more negative during five days of N (P, -47 ± 17 vs. N, -108 ± 24 mmol; P < 0.05). The effect of N and B on Na balance were independent. In conclusion, short-term administration of N: 1) increases CI and reduces TPRI in the post-diuretic state; 2) blunts B-induced increase in PAldo without modifying the rise in PRA; 3) does not change B kinetics or dynamics or the post-diuretic period of renal Na retention; 4) causes negative Na balance which is additive with that produced by B.