Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis.

Disease-modifying osteoarthritis drugs (DMOADs) should reach their intra-tissue target sites at optimal doses for clinical efficacy. The dense, negatively charged matrix of cartilage poses a major hindrance to the transport of potential therapeutics. In this work, electrostatic interactions were utilised to overcome this challenge and enable higher uptake, full-thickness penetration and enhanced retention of dexamethasone (Dex) inside rabbit cartilage. This was accomplished by using the positively charged glycoprotein avidin as nanocarrier, conjugated to Dex by releasable linkers. Therapeutic effects of a single intra-articular injection of low dose avidin-Dex (0.5 mg Dex) were evaluated in rabbits 3 weeks after anterior cruciate ligament transection (ACLT). Immunostaining confirmed that avidin penetrated the full cartilage thickness and was retained for at least 3 weeks. Avidin-Dex suppressed injury-induced joint swelling and catabolic gene expression to a greater extent than free Dex. It also significantly improved the histological score of cell infiltration and morphogenesis within the periarticular synovium. Micro-computed tomography confirmed the reduced incidence and volume of osteophytes following avidin-Dex treatment. However, neither treatment restored the loss of cartilage stiffness following ACLT, suggesting the need for a combinational therapy with a pro-anabolic factor for enhancing matrix biosynthesis. The avidin dose used caused significant glycosaminoglycan (GAG) loss, suggesting the use of higher Dex : avidin ratios in future formulations, such that the delivered avidin dose could be much less than that shown to affect GAGs. This charge-based delivery system converted cartilage into a drug depot that could also be employed for delivery to nearby synovium, menisci and ligaments, enabling clinical translation of a variety of DMOADs.

Diagnosis of Mycobacterium bovis infection in cattle by use of the gamma-interferon (Bovigam) assay.

The strategic use of the gamma-interferon (IFN-gamma) assay (Bovigam) can provide a means for the early identification of Mycobacterium bovis infected cattle, thus ensuring their removal from an infected herd. When used in parallel with the tuberculin test, it is capable of identifying infected cattle, which might otherwise not be detected until later, if at all. The early detection and removal of these animals reduces the risk that they will become a source of infection for other cattle. When targeted in herds of high prevalence the benefits to the herd owner directly concerned can be considerable as the assay provides a means of shortening the period of restriction for such herds. This serves to generate confidence among herd owners and other stakeholders that effective schemes, based on sound scientific principles, can be developed to eradicate tuberculosis from infected cattle populations.

The allergic patient who is noncompliant and abusive: dealing with the adverse experience.

The field of Allergy-Immunology is involved with the care of patients with chronic illness. The care of these patients is enhanced when the physician has established good rapport with the patient. The noncompliant, disruptive behavior of some patients can try the patience of even the most understanding physicians and, in turn, impede the delivery of care. Interactions with this type of patient may leave the physician with feelings of guilt, frustration, and helplessness. We review such an encounter with the purpose of describing how to deal with this type of patient and to guide the physician in responding to this adverse behavior. Such patients will usually require limits to be set on behavioral acting out for their own best interest. Further, it is often necessary to make continued care contingent on compliance with the ground rules set. The physician must be aware of his or her adverse feelings toward the patient and be able to interpret the behavior in the context of the psychiatric disorder so that appropriate psychologic help for the patient can be provided.

Hypogammaglobulinemia associated with cytomegalovirus pneumonia.

Transient but profound hypogammaglobulinemia occurred during cytomegalovirus (CMV) pneumonia in a patient who developed striking declines in number of T lymphocytes. A 66-year-old, female, human immunodeficiency virus-negative patient requiring long-term hemodialysis had normal serum immunoglobulin concentrations before the onset of CMV pneumonia (IgG, 1070-1470 mg/dl; IgA, 94-102 mg/dl; IgM, 30-48 mg/dl). During the pneumonia episode, serum immunoglobulin concentrations were profoundly reduced (IgG, 440 mg/dl; IgA, 40 mg/dl; IgM, 25 mg/dl). Total lymphocytes declined from 3048/mm3 to 212/mm3 with reductions in CD4+CD45- lymphocytes (inducers of B cells) to 9% (nl, 24%-32%) and CD4+CD45+ lymphocytes (inducers of suppressor T cells) to 4% (nl, 14%-22%). CD8 lymphocytes were reduced to 5% (nl, 19%-31%). As the pneumonia resolved, serum immunoglobulin concentrations returned to normal. This is one of the few reported instances of CMV infection apparently causing hypogammaglobulinemia.

A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol.

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

Comparison of once daily atenolol, nitrendipine and their combination in mild to moderate essential hypertension.

1. The aim of the study was to compare the efficacy and the tolerability of treatment with atenolol (50-100 mg once daily), nitrendipine (20-40 mg once daily) and their combination (atenolol 50 mg + nitrendipine 20 mg) once daily in patients with mild to moderate essential hypertension. 2. The study was a randomised, double-blind, placebo controlled parallel groups design: blood pressures were measured at 'trough' effect (i.e. 24 h after dosing) to assess the adequacy of once-daily treatment. 3. Mean blood pressures (mm Hg) recorded on four occasions over 12 weeks of treatment were significantly lower both with atenolol (155/97 sitting: 155/104 standing) and with the combination of atenolol plus nitrendipine (153/96 sitting: 152/104 standing) than with placebo (169/108 sitting: 169/114 standing). Nitrendipine alone had no significant effect on blood pressure 24 h after dosing (165/104 sitting: 165/110 standing). 4. Withdrawals due to adverse effects were more common during treatment with nitrendipine: 7/32 of the patients experienced adverse effects attributable to intense systemic vasodilatation (e.g., flushing, erythema, headache). 2/37 patients taking atenolol were withdrawn: one because he developed a psoriatic rash and the other because of impaired peripheral circulation. Of the 35 patients taking combination treatment, two were withdrawn: one developed headaches and dyspnoea, and the other asthma. 5. The results suggest that once daily dosing with nitrendipine does not control blood pressure throughout the 24 h period in the majority of patients, and is associated with a considerable burden of adverse effects. Combination treatment was better tolerated but appeared to offer no advantages over atenolol alone in terms either of blood pressure control or adverse effects.

Infarct size reduction: a review of clinical trials.

Early studies in experimental animals and in humans indicated the need to examine the feasibility of infarct size reduction by the early treatment of patients recruited to well-designed clinical trials. The extensive experience with beta-adrenoceptor blockers and the comparatively recent data generated with the use of calcium antagonists in patients with acute myocardial infarction are reviewed. Early intravenous administration of beta-adrenoceptor blockers in suitable patients appears to produce genuine infarct size reduction (approximately 20%) compared with controls, whereas calcium channel antagonists have failed to demonstrate such an effect. Possible mechanisms for these findings are discussed.

Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability.

1. In a double-blind, randomised, three-way-crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run-in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. 'Washout' periods were not included. 2. The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone, but the high dose nifedipine combination was no more effective than the low dose nifedipine combination. Sitting systolic BP (+/- s.e. mean) at the end of each period was 174 +/- 5 mm Hg after the atenolol run-in, 170 +/- 5 mm Hg with atenolol alone, 156 +/- 5 mm Hg with the low dose combination and 158 +/- 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/- 2 mm Hg, 106 +/- 2 mm Hg, 97 +/- 2 mm Hg and 99 +/- 2 mm Hg respectively. 3. Side-effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side-effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/- 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ageing on the disposition of nifedipine and atenolol.

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half-life in the elderly was significantly longer (8.8 +/- 0.9 h) compared with that in the young (5.8 +/- 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post-dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.

Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial.

Men aged 40-64 years with mild to moderate hypertension [diastolic blood pressure (DBP) 100-130 mmHg] were randomized to treatment with a diuretic (n = 3272) or a beta-blocker (n = 3297), with additional drugs if necessary, to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease (CHD) events and death. Patients with previous CHD, stroke or other serious diseases, or with contraindications to diuretics or beta-blockers were excluded. If normotension (DBP less than 95 mmHg) was not achieved by monotherapy, other antihypertensive drugs were added, but the two basic drugs were not crossed over. Patients were assessed at 6-monthly intervals. The mean follow-up for end-points was 45.1 months. Blood pressure (BP) side effects and end-points were recorded in a standardized manner. Entry characteristics and the BP reduction achieved were very similar in both treatment groups. All analyses were made on an intention-to-treat basis. The incidence of CHD did not differ between the two treatment groups. The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group. Total mortality and the total number of end-points were similar in both groups. The percentage of patients withdrawn due to side effects was similar, whereas the number of reported symptoms, according to a questionnaire, was higher for patients on beta-blockers. The incidence of diabetes did not differ between the two groups. Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers, and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD. Beta-blockers and thiazide diuretics were approximately equally well tolerated. The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group. Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications, including CHD, to a different extent.

Calcium antagonists: a review of the recent comparative trials.

A review of published studies was undertaken to assess the efficacy and patient tolerability of calcium antagonists compared with established antihypertensive therapy, i.e. beta-blockers and diuretics. Randomized controlled trials undertaken in Caucasian patients with mild to moderate hypertension were evaluated. Only 12 trials fulfilled the criteria for inclusion in the review and they differed considerably with regard to design, method of analysis, and drug and dose regimen used; a formal pooled analysis of the data was not feasible. Few trials demonstrated significant differences in blood pressure control between treatments. Side effects were rarely seen, or were not assessed, and the number of patients studied was relatively small. Two large unpublished trials have recently evaluated the slow-release twice-daily formulation of 20 mg nifedipine, 50 mg atenolol and the fixed combination of 50 mg atenolol + 20 mg nifedipine, using a randomized double-blind crossover design. Mean blood pressure with atenolol was consistently lower than with nifedipine although this achieved statistical significance in only one study (P less than 0.01). Fixed combination therapy gave a greater antihypertensive effect than either atenolol or nifedipine administered alone (P less than 0.05 to P less than 0.001). Side effects were most common with nifedipine treatment, less common with combination therapy and occurred least commonly with atenolol alone (P less than 0.001). In one study involving 44 patients (aged 20-70 years), side effects attributable to peripheral vasodilation secondary to nifedipine therapy, e.g. flushing and sweats, were significantly greater (P less than 0.05) with nifedipine (n = 11) than with atenolol (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of the pharmacokinetics and pharmacodynamics of atenolol, hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients.

Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.

Bioavailability in man of atenolol and chlorthalidone from a combination formulation.

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drugs as a fixed combination ('Tenoret 50'), as a free combination, and individually, at doses of 50 mg atenolol and 12.5 mg chlorthalidone. There were no statistically or clinically significant differences between the three treatments of atenolol in terms of individual blood levels, areas under the curve, and urinary excretion. The mean half-lives were between 5 and 7 h, in agreement with other published data. The variation in peak systemic levels is less than that observed for a number of other beta-blocking drugs and is of the same order as seen in other investigations involving atenolol. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet. The mean peak blood concentrations of chlorthalidone were 0.94, 1.00, and 0.99 micrograms ml-1 for the fixed and free combinations and the chlorthalidone tablet, respectively. The mean areas under the curve were also similar as were the mean half-lives and urinary recovery. There were no statistically or clinically significant differences between the three treatments. Thus the bioavailability of chlorthalidone from the fixed combination is equivalent to that from the free combination and from the chlorthalidone tablet. It is concluded that combining chlorthalidone and atenolol in a single tablet does not affect the systemic bioavailability of either component.

Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol.

The influence of chronic therapy with nifedipine on the pharmacokinetics of propranolol 80 mg twice daily, metoprolol 100 mg twice daily and atenolol 100 mg once daily was investigated in eight healthy volunteers. Nifedipine 10 mg three times daily did not affect the pharmacokinetics of metoprolol and atenolol whereas nifedipine shortened the time to peak plasma concentration for propranolol by about 1 h. Propranolol, metoprolol and atenolol provoked comparable decreases in heart rate measured at rest and during exercise. The beta-adrenoceptor blocking properties of propranolol, metoprolol and atenolol were not affected by concomitant therapy with nifedipine. The present study did not show significant pharmacokinetic and pharmacodynamic interactions between nifedipine and lipophilic beta-adrenoceptor blockers.

Pharmacokinetics and pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol.

Treatment of angina pectoris with beta-adrenoceptor antagonists and verapamil in combination is effective and increasingly common. The study reported here was designed to show whether the pharmacokinetics of verapamil are influenced by concurrent treatment with three different beta-adrenoceptor blockers, and whether there is any pharmacodynamic interaction between these drugs. Twelve healthy volunteers (eight men, four women) aged 21-25 years and weighing 48-82 kg consented to participate in the study. They received verapamil 50 mg three times daily for four 1-week periods, each separated by a 1 week 'washout' period. During three of the four treatment periods, the subjects took either atenolol 100 mg once daily, metoprolol 100 mg twice daily or propranolol 80 mg twice daily; in the remaining period they took verapamil alone. The concentration/time curve and plasma elimination half-life of verapamil and norverapamil, its major metabolite, were not influenced by 1 weeks co-administration atenolol, metoprolol or propranolol. As expected, co-administration of each of the beta-adrenoceptor blockers significantly reduced exercise heart rate when compared with verapamil alone.

The effect of cimetidine on the relative cardioselectivity of atenolol and metoprolol in asthmatic patients.

The effects of chronic cimetidine therapy on the pharmacodynamic properties of atenolol and metoprolol were assessed in eight asthmatic patients using a placebo-controlled trial. When atenolol and metoprolol were administered at doses which achieved an equivalent degree of beta1-adrenoceptor blockade, metoprolol caused a significantly greater reduction in mean forced expiratory volume in one second (FEV1). This demonstrates the greater cardioselectivity of atenolol. The reductions in mean FEV1 induced by either atenolol or metoprolol were each unaffected by cimetidine. Plasma levels of each of the beta-adrenoceptor blockers were not affected by the addition of cimetidine. The FEV1 in one patient was further reduced when cimetidine was administered with metoprolol, although there was no corresponding change in plasma levels of drug. In this patient there was no such further reduction in FEV1 with atenolol. This study has not provided evidence for a pharmacodynamic interaction between cimetidine and either atenolol or metoprolol, but further studies are indicated.