Tigecycline use in the outpatient parenteral antibiotic therapy setting.

In the context of globally increasing antimicrobial resistance, tigecycline appears to be a useful therapeutic option. The need for prolonged courses for complex infections has prompted consideration of its use via outpatient parenteral antibiotic therapy (OPAT) programmes, although clinical outcomes when used in this setting remain unknown. We retrospectively reviewed the patient characteristics and outcomes of 11 patients who received tigecycline, most commonly delivered as 100 mg once daily, via OPAT at three tertiary Australian hospitals. Rates of co-morbidity and prior antibiotic use were high. Patients had a wide range of infections including bone and/or joint (n = 5), intra-abdominal (n = 3), lower respiratory tract (n = 2) and parapharyngeal abscess (n = 1). Mycobacterial species (n = 5) were the most frequent pathogen, and multi-resistant organisms were common (n = 4). The median OPAT duration was 14 days (IQR 6-30). Nausea was encountered in 45 % of cases. At completion of OPAT, 1 patient (9 %) was cured, 2 (18 %) had improved and 8 (73 %) failed therapy. Failure occurred due to either progression or non-response of infection (n = 4), re-admission (n = 3), premature cessation of tigecycline due to nausea (n = 3) or death (n = 1). Whilst OPAT delivery of tigecycline is a therapeutic option, when used as second-line therapy for complex, often multi-resistant infections in patients with multiple comorbidities, high rates of clinical failure, readmissions and adverse effects, especially nausea, should be anticipated.

The pharmacokinetics of ganciclovir during prolonged intermittent kidney replacement therapy in a cardiac transplant recipient.

Ganciclovir, a guanine analogue, is used intravenously (IV) first-line for the prophylaxis and treatment of cytomegalovirus (CMV) infection in solid organ transplant recipients. The pharmacokinetics (PK) of ganciclovir are highly variable, with myelosuppression occurring at high concentrations. Ganciclovir is primarily renally excreted as the parent compound, and clearance is significantly reduced in renal impairment. Acute kidney injury (AKI) is a common post-operative complication of cardiac transplantation, reducing the clearance of ganciclovir. In the intensive care unit (ICU), AKI is often managed by kidney replacement therapy (KRT). One form of KRT, prolonged intermittent kidney replacement therapy (PIKRT) is increasingly used for cost and flexibility advantages. Ganciclovir dosing recommendations are available for varying degrees of renal impairment and KRT, except for PIKRT. In this case of cardiac transplantation, complicated by anuric AKI, a ganciclovir dose of 2.0-2.5 mg/kg of adjusted body weight given after each PIKRT session was demonstrated to achieve PK targets.

The efficacy of locally applied aspirin and acetaminophen in postoperative pain after third molar surgery.

This study evaluated the efficacy of and investigated the site of action of aspirin and acetaminophen placed directly into tooth sockets after bilateral third molar surgery under local anaesthesia. On completion of surgery, 12 patients received in random, blind order either a suspension of aspirin in a methyl cellulose gel (100 mg/ml) in their tooth sockets and an oral placebo or the methyl cellulose alone in their sockets and an oral dose of aspirin (50 mg). The remaining 12 patients were treated in the same fashion with use acetaminophen. Patients were asked to record their pain, at intervals, over an 8-hour period on a 10 cm visual analog scale. Significantly less pain (p less than 0.05) was recorded throughout the 8-hour investigation period after both locally placed drugs than after placebo. There was no adverse effect on healing. The peripheral activity of aspirin is confirmed, and our findings suggest that acetaminophen has a significant peripheral effect in mediating its analgesic properties in postoperative pain after third molar surgery.

Predicting the dose of warfarin for therapeutic anticoagulation.

The validity of a previously described technique for predicting warfarin requirements based on the anticoagulant response to a fixed loading dose was assessed prospectively in 57 patients. There was a close relationship between the predicted and initially observed daily warfarin dose required to maintain the patient within the therapeutic range for anticoagulation. The significant relationship between predicted and observed maintenance dose persisted at 4 and 12 weeks although it decreased with increasing time. The relationship between observed and predicted maintenance requirement of warfarin was not affected by the concomitant use of intermittent intravenous injections of heparin when 9 hr was allowed to elapse between the previous dose of heparin and the thrombotest estimation on which the prediction was based. It is concluded that the method is valuable in predicting an individual's warfarin requirement, although it does not obviate the need for regular monitoring of anticoagulant control.

Gilbert's syndrome and drug metabolism.

Gilbert's syndrome is an inherited disorder which is characterised by unconjugated hyperbilirubinaemia. In patients with Gilbert's syndrome, both bilirubin clearance and in vitro hepatic microsomal uridine diphosphoglucuronyl transferase (UDPGT) activity are reduced. In addition, there is evidence suggesting impaired hepatic uptake of bilirubin in Gilbert's syndrome. Glucuronidation of a number of substrates appears to be impaired in Gilbert's syndrome, but the significance of the reported changes in oxidation and acetylation are less clear.

Influence of allopurinol on drug metabolism in man.

1. Elimination rates of phenylbutazone and warfarin after single oral doses in human volunteers, and steady-state plasma concentrations of these drugs in patients have been measured before, during and after administration of allopurinol.2. Allopurinol, in usual clinical doses, had no significant influence on the elimination rate of either drug in the group of volunteers as a whole although in a few individuals an apparent inhibitory effect was observed.3. No significant changes in the steady-state plasma concentrations of either phenylbutazone or warfarin were observed in patients during the administration of allopurinol.4. It is concluded that although allopurinol may have an apparent inhibitory effect on drug elimination in a few individuals, its administration to most patients on anticoagulant therapy is unlikely to alter dose requirements.

The effects of intraventricular 6-hydroxydopamine on body temperature and arterial blood pressure in cats and rabbits.

1 In unanaesthetized cats, the administration of 6-hydroxydopamine (6-OHDA), 750 mug, via the lateral cerebral ventricle produced a pronounced fall in rectal temperature but only a slight fall when repeated 7 days later. At this time hypothalamic noradrenaline concentration had diminished to 4% of control.2 In these animals, the hypothermic response to exogenous noradrenaline, 100 mug, given via the same route was uninfluenced by pretreatment with 6-OHDA.3 In unanaesthetized rabbits, intraventricular noradrenaline, 100 mug, produced a rise in rectal temperature and a biphasic effect on arterial pressure, a rise lasting 30 min followed by a fall.4 Intraventricular 6-OHDA, 750 mug, in unanaesthetized rabbits produced a rise in body temperature and a rise in arterial pressure. The same dose given to rabbits depleted of central noradrenaline with central 6-OHDA produced rises in body temperature and arterial pressure of similar magnitude, but of slower onset.5 These results suggest that intraventricular 6-OHDA releases noradrenaline from central neurones and that these neurones subserve thermoregulatory functions in both species. In the rabbit, central noradrenergic neurones can raise arterial pressure.

Influence of the duration of experimental fever on salicylate antipyresis in the rabbit.

1. Steady state fever has been produced in rabbits with a priming injection followed by a sustaining infusion of homologous plasma containing endogenous pyrogen (EP). This fever appears to last as long as the infusion continues.2. Intravenous salicylate given 1 h after the start of the EP infusion produced only a small antipyretic effect. The same dose of salicylate given 4 h after the start of an EP infusion resulted in rapid and progressive defervescence. Intermediate antipyretic responses were obtained when salicylate was administered intravenously 2 and 3 h after the start of an EP infusion.3. Less than 1% of the systemic dose, when injected into a lateral cerebral ventricle, produced a significantly smaller response at 1 h than at 4 h after the start of an EP infusion. At both these times the fall in temperature following the intraventricular salicylate injection was dose dependent, but the slope of the dose-response line was significantly steeper at 4 h than at 1 hour.4. It is suggested that salicylates produce their antipyretic effects by antagonizing the action of EP within the nervous system, and that the hypothalamic EP concentration falls during the course of an EP infusion.

Aryl hydrocarbon hydroxylase activity and psoriasis.

Aryl hydrocarbon hydroxylase (AHH) has been measured in the skin, jejunum and liver of normal and psoriatic individuals. We have been unable to confirm previous reports of an abnormality in AHH activity in patients with psoriasis. Re-examination of the laboratory records on which the original reports were based leads us to doubt their veracity and validity.

Major differences between lung, skin and liver in the microsomal metabolism of homologous series of resorufin and coumarin ethers.

Phenoxazone and a homologous series of its ethers (methoxy to octoxy plus benzyloxy), and coumarin and a series of its ethers (methoxy to propoxy), were metabolized by liver, lung and skin microsomes of normal adult female BALB/c mice. For each series of substrates, and with each tissue, clear structure-activity relationships were seen, relating metabolic activity to the length of the ether side-chain. With the coumarin series of substrates the structure-activity relationships were almost identical in the three tissues, with liver more active than lung and lung more active than skin. Liver, lung and skin microsomes each showed very different structure-activity relationships, however, for metabolism of the phenoxazone series of substrates. Benzyloxyphenoxazone was metabolized almost twice as fast in lung as in liver, but for the other phenoxazone substrates the activities were much greater in liver than in lung or skin. Liver, lung and skin microsomal propoxy- and benzyloxyphenoxazone dealkylase activities differed in their sensitivities to inhibition by metyrapone and alpha-naphthoflavone. The structure-activity relationship and inhibitor data for the phenoxazone substrates are consistent with a view that mouse lung and sking cyt. P-450 are predominantly similar to phenobarbitone-induced and 3-methylcholanthrene-induced forms of hepatic cyt. P-450 respectively. The results also show that the pattern of microsomal metabolism of xenobiotics in lung and skin cannot be reliably predicted from that in liver.

The acute and subchronic effects of ketoconazole on hepatic microsomal monooxygenases in the rat.

Female adult Wistar rats were treated with single or repeated doses of ketoconazole ranging from 10 mg/kg to 100 mg/kg. Single dose treatment produced inhibition of hepatic microsomal ethoxyresorufin O-deethylation (EROD) and aldrin epoxidation (AE) 2 hr after oral dosing. Twenty-four hours after a single dose, inhibition was still demonstrable after the low dose of 10 mg/kg, but at higher doses increased microsomal activity was apparent. After 7 days repeated dosing liver weight and microsomal protein content were increased in a dose-dependent fashion. EROD and AE were induced at all doses after repeated treatment when the increase in liver size was considered. These effects were seen at doses within the antimycotic therapeutic range and add support to the suggestion that reported drug interactions with ketoconazole in man are due to the effects of this drug on hepatic microsomal activity.

Flumecinol for the treatment of pruritus associated with primary biliary cirrhosis.

OBJECTIVE: To determine whether flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol, Zixoryn) is effective in ameliorating pruritus of cholestasis, particularly in primary bilary cirrhosis. METHODS AND RESULTS: 50 patients (46 with primary biliary cirrhosis, PBC) took oral flumecinol 600 mg or identical placebo once weekly for 3 weeks. Patients assessed pruritus by scoring a daily 100 mm visual analogue scale (VAS; 0 = no itch, 100 = severe, continuous, day and night intolerable itch). Quality of life was similarly measured. Patients scored the VAS daily for a 7-day baseline and for a further 21 days. Subjectively, pruritus improved in 13 of 24 on flumecinol and 10 of 26 on placebo (chi 2 = 1.24, P = 0.27). Median difference in fall in VAS pruritus score between baseline week (mean score for each individual used) and the last week was 8.0 [95% confidence interval (CI) -2.1 to 20.8] and for VAS quality of life was 5.0 (95% Cl 0.4 to 13.0) both in favour of flumecinol over placebo. Later, 19 patients (all PBC) were randomised to flumecinol 300 mg or placebo daily for 3 weeks. Subjectively, pruritus improved in 7 of 10 on flumecinol and 1 of 9 on placebo (Fisher's exact test, P = 0.02). Median difference in fall in VAS pruritus score was 19.8 mm (95% CI 3.3 to 40.7 mm) in favour of flumecinol over placebo and for quality of life was 3.5 mm (95% Cl -5.9 to 24.9 mm). Flumecinol did not significantly affect liver function tests, antipyrine clearance or serum total bile acids, and was not associated with any significant side-effects. CONCLUSION: Flumecinol was safe at the above doses and short term treatment with 300 mg daily, significantly ameliorated pruritus in primary biliary cirrhosis.

The effect of gastritis on human gastric alcohol dehydrogenase activity and ethanol metabolism.

BACKGROUND: Gastric mucosal alcohol dehydrogenase (ADH) may decrease the bioavailability of ingested ethanol. Because this enzyme is found in highest concentrations in the superficial gastric mucosa, diffuse abnormalities of this tissue could lead to a decrease in the first pass metabolism of ethanol. METHODS: Thirty-three adult subjects undergoing routine upper gastrointestinal endoscopy had gastric biopsies performed for assessment of gastric histology and the measurement of gastric ADH activity. Twenty of these subjects underwent separate oral dosing and intravenous infusion of ethanol (0.15 g/kg body weight) in order to determine the first pass metabolism, and hence bioavailability, of ethanol. RESULTS: Gastric histology was normal in 10 of the biopsies, showed chronic gastritis alone in 13 and significant glandular atrophy (i.e. atrophic gastritis) in a further 10. Gastric ADH activity in specimens with normal gastric histology was significantly higher than those with chronic gastritis (P = 0.02), and was further decreased in those specimens with significant atrophy (P < 0.00001). However, no correlation was found between gastric ADH activity and the first pass metabolism of ethanol (r = 0.09, P = 0.9). CONCLUSIONS: These results suggest that although gastric ADH activity was decreased in individuals with abnormal gastric mucosa, ethanol bioavailability was not affected by gastric ADH activity. These data support the view that gastric ADH does not play a significant role in the first pass metabolism of alcohol.

Absence of withdrawal effects of ritanserin following chronic dosing in healthy volunteers.

The possible development of withdrawal symptoms following abrupt discontinuation of ritanserin after chronic administration of 10 mg daily for 8 weeks was investigated in a placebo controlled trial in 40 healthy subjects. The study consisted of two phases. In the first phase, under single blind conditions, all subjects received placebo for 2 weeks followed by a single daily dose of ritanserin (10 mg) for 8 weeks. In the second phase, under double blind conditions, subjects were randomised to receive either placebo or to continue on ritanserin (10 mg) for a further 4 weeks. Psychological assessments were performed at the start of and at intervals throughout the study. Levels of anxiety, concentration, quality of sleep and morning vigilance were measured throughout by daily visual analogue scales. No significant changes were detected in any of the measures in the group of subjects who received ritanserin compared to the group who received placebo during the second phase of the study. Ritanserin discontinuation following chronic dosing in healthy volunteers does not appear to be associated with withdrawal symptoms.

Metabolism of aldrin to dieldrin by rat skin following topical application.

Metabolism of the pesticide aldrin to dieldrin in the rat was studied following topical and ip administration of 0.1-10 mg aldrin/kg body weight. When aldrin was applied topically to the dorsal skin at a dose of 10 mg/kg body weight, absorption was less efficient than after ip administration; lower blood levels of aldrin and dieldrin were seen and peak dieldrin levels were delayed. After ip administration of 1 or 10 mg aldrin/kg body weight, dieldrin was found at similar concentrations in the dorsal and ventral skin 7 hr later, whereas 7 hr after topical administration of 10 mg aldrin/kg, the dieldrin concentration in the skin at the dorsal site of application was four times higher than that at a ventral skin site. Similar differences in dieldrin concentrations between dorsal and ventral skin persisted throughout the 7-hr period following topical application. The results indicate that topically applied aldrin is metabolized to dieldrin in the skin during absorption, but the overall proportion of metabolism that takes place in the skin is small compared with the contribution of the liver. Dieldrin was not detected in the ventral skin remote from the application site 1 hr after topical application of aldrin, whereas a dieldrin concentration of 2.2 nmol/g was detected in the skin of the application site at this time; more than 99% of this dieldrin was probably formed locally by dermal metabolism of percutaneously absorbed aldrin. The efficiency of conversion of applied aldrin to dieldrin decreased with increasing aldrin dose in the range 0.1 to 10 mg/kg.

Human liver and plasma aspirin esterase.

The plasma, in addition to the liver, is a major site of hydrolysis of aspirin. Human plasma and liver aspirin esterase activities in samples from a group of patients varied over a two fold range and there was a significant correlation between individual plasma and liver activities. Human liver aspirin esterase was present in the cytosolic and microsomal fractions. Cytosolic and microsomal enzymes had different activities and apparent affinities for aspirin.

Incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients in general medical practice.

This investigation examines the incidence of phenytoin-induced gingival overgrowth in a population of epileptic patients who attend General Medical Practices for treatment of their epilepsy and compares the gingival changes with an otherwise healthy group of patients. The plaque score, gingival index, and gingival overgrowth did not differ significantly between the two groups (P > 0.05). A significant correlation was observed between plaque score and gingival overgrowth in the phenytoin-treated patient, but in this group there was no correlation between gingival overgrowth and salivary concentration of the drug. The overall incidence of clinically significant overgrowth (13%) is considerably less than in other studies.

The biochemical and haemodynamic effects of adrenaline in lignocaine local anaesthetic solutions in patients having third molar surgery under general anaesthesia.

The effects of adrenaline-containing and adrenaline-free lignocaine local anaesthetic solutions injected in doses consistent with clinical practice on plasma potassium concentration, blood glucose levels and haemodynamic responses were investigated in 20 patients having third molar surgery under general anaesthesia. All patients received a standard general anaesthetic regime. Ten patients were given 4.0 ml of 2% lignocaine as an inferior dental and long buccal block during their general anaesthetic and the other 10 received 4.0 ml of 2% lignocaine containing 1:80000 adrenaline in the same manner. There were no significant differences between treatments in blood pressure or heart rate. However, there were significant differences between treatments in plasma potassium concentration and blood glucose levels.

Study of United Kingdom product licence applications containing new active substances, 1987-9.

OBJECTIVES: To investigate the fate of product licence applications containing new active substances in relation to their degree of innovation and therapeutic category. To assess the numbers of volunteers and patients exposed to a new active substance when marketing autorisation is first sought. DESIGN AND SETTING: Observational study of records for each licence application submitted to the United Kingdom licensing authority for marketing authorisation from 1987 to 1989. SUBJECTS: 118 product licence applications containing one or more new active substances. MAIN OUTCOME MEASURES: Success of application for product licence as assessed by the decision of the Committee on Safety of Medicines to advise the granting of a licence (with or without conditions) or provisionally advise its refusal on the grounds of quality, safety, or efficacy. Assessment of numbers of volunteers and patients exposed to each substance during premarketing studies and clinical trials, and the numbers of treated patients available for an assessment of safety. RESULTS: 118 relevant product licence applications were submitted during the review. Although 60% (52/86) of semi-innovative products fell into one of three therapeutic categories (cardiovascular, central nervous system, or anti-infective agents), only 41% (13/32) of fully innovative products fell into these categories. 47 applications were granted (conditionally or unconditionally) but the success rate for fully innovative products (56%, 18/32) was greater than that for semi-innovative products (34%, 29/86). The number of volunteers and patients exposed to a new product at submission varied widely and tended to be greater for successful applications. CONCLUSION: The results suggest a broadening of the pharmaceutical industry's research and development programmes and that a more liberal licensing policy exists for fully innovative products than for semi-innovative products. The relatively limited exposure of patients to new active substances at licensing underlines the importance of rigorous postmarketing surveillance.

Review of company postmarketing surveillance studies.

OBJECTIVES: To review postmarketing surveillance studies sponsored by the pharmaceutical industry since the introduction of voluntary guidelines in 1987 and to evaluate their contribution to monitoring drug safety. DESIGN: Retrospective analysis of the information submitted to the Medicines Control Agency on postmarketing surveillance studies. SETTING: United Kingdom. MAIN OUTCOME MEASURES: Study designs, projected and actual sample sizes, provision of interim and final reports, number of suspected serious adverse reactions reported, identification of new drug safety hazards. RESULTS: 31 studies had been conducted under the guidelines, of which 27 were prospective and four retrospective. Nine studies had at least one comparator group, the remainder were uncontrolled. The median projected sample size for the studies was 5600 patients. Only five studies had achieved at least 75% of the projected sample size. 11 studies had been abandoned, predominantly because of difficulties in recruitment, and 15 were ongoing. One study had identified an important new safety hazard. CONCLUSIONS: Company postmarketing surveillance studies have made only a limited contribution to the assessment of drug safety, principally because of weak study designs and difficulties in recruitment. The guidelines require modification to take this experience into account.