Sole Therapeutic Agent Research Articles

Exposure to blue light reduces antimicrobial resistant Pseudomonas aeruginosa isolated from dog ear infections.

Pseudomonas aeruginosa is a leading cause of canine otitis externa. Enrofloxacin is often applied topically to treat this condition, although recalcitrant and recurring infections are common. There is evidence that exposure to blue light (400-470 nm) has a bactericidal effect on P. aeruginosa and other microorganisms. In the present study, we tested the biocidal effect of blue light (375-450 nm), alone or in combination with enrofloxacin, against six isolates of P. aeruginosa from dogs with otitis externa (5 of which were resistant to enrofloxacin). Treatment of planktonic cell cultures with blue light resulted in significant (p < 0.5) reductions in Colony Forming Units (CFU) for all seven strains tested, in some cases below the limit of detection. The greatest bactericidal effect was observed following exposure to light at 405 nm wavelength (p < 0.05). Exposure to blue light for 20 min usually resulted in a greater reduction in Pseudomonas aeruginosa than enrofloxacin treatment, and combination treatment typically resulted in the largest reductions in CFU. Analysis of the genome sequences of these strains established that enrofloxacin resistance was likely the result of a S466F substitution in GyrB. However, there was no clear association between genotype and susceptibility to blue light treatment. These results suggest that blue light treatment, particularly at 405 nm wavelength, and especially in combination with enrofloxacin therapy, could be an effective treatment for otherwise recalcitrant canine otitis externa caused by Pseudomonas aeruginosa. It may also provide a way of extending the usefulness of enrofloxacin therapy which would otherwise be ineffective as a sole therapeutic agent.

Novel Use of Ranolazine as an Antiarrhythmic Agent in Atrial Fibrillation.

To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery. English-language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated. The use of ranolazine monotherapy has been evaluated in 2 clinical trials. In the RAFFAELLO trial, higher doses of ranolazine showed a trend toward lower AF recurrence versus placebo ( P = 0.053), but further evidence is needed to support its use as a sole therapeutic agent. Ranolazine has shown utility in a limited number of studies as an adjunctive agent, which is critical for those in whom standard therapy is inadequate or the adverse event profile precludes optimized standard therapy. In the HARMONY trial, ranolazine 750 mg and dronedarone 225 mg twice daily reduced the AF burden by 59.1% from baseline ( P = 0.008 vs placebo). In a trial by Koskinas and colleagues, patients receiving ranolazine 1500 mg once and intravenous amiodarone had a higher conversion rate than those receiving amiodarone alone ( P = 0.024). There are also promising studies for the prevention and treatment of post-cardiothoracic surgery AF, which require further investigation. Ranolazine's pharmacological properties and available evidence suggest potential for its use in AF.

Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus)

Clinically normal koalas (n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady-state volume of distribution (Vss ) were 0.31 (0.11-0.55) L/h/kg and 0.92 (0.38-1.40) L/kg, respectively. The elimination half-life (t1/2 ) was much shorter than in many species (i.v.: median 2.25, range 0.98-6.51 h; p.o.: 4.69, range 2.47-8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20-0.97). Absorption rate-limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution (Varea ) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h.

Effect of Immunomodulating and Antiviral Agent of Medicinal Mushrooms (Immune Assist 24/7TM) on CD4+ T-Lymphocyte Counts of HIV-Infected Patients

Immune enhancement through the use of natural products is a potentially valuable therapeutic modality in HIV-infected people, especially those who are not good candidates for aggressive ARV therapy. One such immune enhancement, a medicinal mushroom product from the United States, is Immune Assist 24/7. In this study the effect of Immune Assist 24/7, which is a naturally derived immune-modulating and antiviral agent, on CD4+ T-lymphocyte counts was evaluated in 8 HIV-infected patients at the Sunyani Regional Hospital (Ghana). The subjects were administered three tablets of 800 mg Immune Assist 24/7 once daily (2.4 g/day) and peripheral blood samples were drawn at baseline, day 30, and day 60, and the CD4+ count measured. The study revealed that Immune Assist 24/7, used as a sole therapeutic agent without additional ARV drugs, significantly increased CD4+ T-lymphocyte populations in all of the patients. In one patient, the CD4+ T-lymphocyte count went from 4 at the baseline, to 170 cells in 60 days, representing an increase of more than 4000%. In another patient, the CD4+ count went from 88 to 470 cells within the same period. Even in the patients with the highest CD4+ counts of around 800, there was a significant elevation in the CD4+ count noted. This study did not deal with the effect of Immune Assist 24/7 on other immune parameters such as CD3+ T-lymphocyte count, natural killer cells count, or viral load among HIV-infected patients. These initial results are promising, and indicate the potential value of further evaluating the effects of Immune Assist 24/7 on other immune parameters and viral load among HIV patients, administered either as a sole therapeutic agent, as an adjuvant with standard ARV therapy, or in comparison with standard ARV therapy alone.

Remission of steroid-resistant nephrotic syndrome due to focal and segmental glomerulosclerosis using rituximab

Therapeutic options are limited in cases of focal and segmental glomerulosclerosis (FSGS) that fail to respond to steroids and calcineurin inhibitors. We describe a case in which steroid-resistant nephrotic syndrome (SRNS) secondary to FSGS did not respond to conventional treatment, but was successfully treated with rituximab. Unlike previous reports in which rituximab was used in conjunction with a calcineurin inhibitor, we present the first case where rituximab was used as the sole therapeutic agent. An 11-month-old boy presented with severe manifestations of primary nephrotic syndrome with a subsequent non-responsive steroid course. A renal biopsy confirmed FSGS, with normal staining for podocin and nephrin. Genetic studies for podocin were normal. The child developed ciclosporin-induced hemolytic uremic syndrome (HUS), and the response to plasma exchange, following ciclosporin withdrawal, was only temporary. A trial of a combination of mycophenolate and dexamethasone did not have any effect on proteinuria or fluid status. Four weekly rituximab infusions at 375 mg/m2/dose induced a complete remission without any adverse effects. This case suggests that rituximab may be used as the sole therapeutic agent in the treatment of SRNS secondary to FSGS, especially in cases where calcineurin inhibitors are contraindicated.

Transient stimulatory effects on pituitary-thyroid axis in patients treated with interleukin-2.

It has been shown that various cytokine therapies may influence thyroid hormone parameters that may lead to serious side effects including nonthyroidal illness. Interleukin-2 is effective in increasing CD4-T cell numbers in human immunodeficiency virus (HIV)-infected patients and it is used in the treatment of various malignant tumours. However, the association of interleukin-2 (IL-2) therapy and thyroid function is not clearly established as serial systematic measurements of thyroid parameters have not been performed with interleukin-2 as the sole therapeutic agent. Therefore, it was the aim of this study to examine prospectively the impact of a 5-day interleukin-2 therapy on thyroid parameters in asymptomatic HIV-infected patients. Twenty male euthyroid patients (mean age, 42.6 +/- 3.2 years; body weight, 73.4 +/- 3.0 kg) received 9,000,000 IU/d interleukin-2. Thyroid function was evaluated by measurements of serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), reverse T3 (rT3), thyroglobulin (Tg), thyroxine-binding globulin (TBG), and anti-thyroid-peroxidase (TPO)-antibodies from day 1-4 and on days 7, 14, 20, 40, 60, 80, and 100. All results are given as mean +/- SD. On day 4, we observed a significant increase that was still within normal range of T4 and T3 (p < 0.05). TSH increased from 1.33 +/- 0.57 to 4.53 +/- 1.39 mU/l (p = 0.0001) and FT4 from 18.1 +/- 4.2 to 48.9 +/- 10.9 pmol/L (p = 0.0001) on day 4 with a gradual decrease thereafter. Normalization to baseline levels for TSH (1.45 +/- 0.75 mU/L) and FT4 (18.1 +/- 3.0 pmol/L) was achieved only on day 14. The increase of FT4 was more pronounced (well in the hyperthyroid range) than the increase in total T4 in the presence of normal TBG and albumin concentrations whereas TBG was not affected. We did not observe changes in anti-TPO-antibody levels up to day 100. Our data clearly demonstrate that the administration of interleukin-2 has a stimulatory effect on the pituitary-thyroid axis. The increase of TSH suggests a central stimulation directed by the action of IL-2 as the major mechanism.

Cabergoline, a long-acting dopamine D 2-like receptor agonist, produces a sustained antiparkinsonian effect with transient dyskinesias in parkinsonian drug-naive primates

Continuous dopaminergic receptor stimulation is now considered as an interesting approach for the control of motor complications often seen in parkinsonian patients treated chronically with levodopa. Cabergoline, which is a long-acting dopamine D 2-like receptor agonist, has been tried recently with good results as an adjunct in patients already on levodopa-therapy. Thus, the present study was designed to test the effects of repeated s.c administration of cabergoline as sole therapeutic agent during a month in 3 drug-naive MPTP parkinsonian monkeys to see whether or not cabergoline, given every other day at 0.25 mg/kg, would have a sustained antiparkinsonian effect and would induce dyskinesias. The animals were rated to quantify the antiparkinsonian as well as the dyskinetic response and gross locomotor activity was monitored by photocells. The averaged locomotor response, initially greatly increased ( ∼ 9 times higher than after saline treatment in the same animals), decreased by ∼ 50% after 2 weeks but was thereafter maintained at this level until the end of the study. The parkinsonian features were improved in a sustained manner in all monkeys and transient dyskinesias (week 1 and 2) were present in 2 of 3 monkeys. After sacrifice receptor binding assays were performed on striatal and pallidal tissues homogenates with tritiated selective ligands and compared with those of 3 normal and 3 MPTP-exposed monkeys otherwise untreated. A significant decrease in dopamine D 2-like receptor density in the putamen (−36% on average vs. untreated MPTP-exposed monkeys) may be involved in the behavioral partial tolerance to antiparkinsonian effect of cabergoline and the disappearance of dyskinesias. A reversal of the supersensitivity of GABA A receptor in the internal segment of the globus pallidus (−15% on average vs. untreated MPTP-exposed monkeys) may also be implicated in this latter behavioral effect.

Treatment of Hirsutism in Women With Flutamide

MARCONDES, JOSE A. M.; MINNANI, SANDRA L.; LUTHOLD, WALTHER W.; WAJCHENBERG, BERNARDO L.; SAMOJLIK, EUGENIUSZ; KIRSCHNER, MARVIN A. Author Information

Treatment of hirsutism in women with flutamide

To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. All women were treated with flutamide 250 mg three times a day for 3 months. Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.

The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia: A double-blind, randomized, placebo-controlled, parallel study

Twenty severely retarded institutionalized epileptic adults with phenytoin-induced gingival hyperplasia were divided into two groups and received a daily 3 mg capsule of either folic acid or lactose for 16 weeks in a randomized, double-blind, parallel study. Serum folate and phenytoin levels were recorded at baseline and on completion of the study. Twelve areas of the gingiva on each patient were graded at 4-week intervals for 16 weeks with respect to the three indexes: hyperplasia, gingival health, and plaque index. There were no significant differences between treatment groups for any of the three indexes over time. The poststudy serum folate levels were three times baseline levels for the active drug group ( p < 0.001) but unchanged in the placebo group. Phenytoin blood levels that began within the therapeutic window (10 to 20 μg/ml) tended to remain within the therapeutic window for both groups, with no reported seizure activity. A single daily oral 3 mg capsule of folic acid did not show efficacy as the sole therapeutic agent in the reduction of phenytoin-induced gingival hyperplasia.

Mesulergine (CU 32-085) in the treatment of Parkinson's disease.

The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.

Clonidine Monotherapy in Mild Hypertension

Elsewhere in this symposium, we have reported on the hormonal and hemodynamic effects of clonidine used as a sole therapeutic agent, 1 Golub MS Thananopavarn C Eggena P Barrett JD Sambhi MP Hormonal and hemodynamic effects of acute and chronic clonidine therapy in patients with mild to moderate hypertension. Chest. 1983; 83: 377-379 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar as well as the role of clonidine monotherapy in treatment of hypertension in the elderly. 2 Thananopavarn C Golub MS Sambhi MP Clonidine in the elderly hypertensive: monotherapy and with a diuretic. Chest. 1983; 83: 410-411 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar This article presents a synthesis and review of the evolution of the concepts in favor of the use of clonidine monotherapy in patients with mild hypertension.

Long-term treatment of Parkinson's disease with bromocriptine.

BRomocriptine (15-75 mg per day) alone or with L-dopa was studied during five to 29 months on 44 patients with Parkinson's disease. Used as sole therapeutic agent, it was found excellent in 12 patients who had never received regular L-dopa treatment either because it was never attempted or because of intolerance from the outset. Its anti-Parkinsonism activity was comparable with L-dopa. The gain was stable in the long term until this report. The side effects of L-dopa were not seen after bromocriptine. In cases where L-dopa had ceased to be active, bromocriptine produced a further improvement if mental deterioration was not associated. In very advanced forms of Parkinson's disease with associated dementia, bromocriptine did not produce durable results. Bromocriptine did not improve the "on-off" effects but reduced a number of the side effects of L-dopa, in particular cardiac, painful contractions, and dyskinesia without "on-off" effects.

The Effect of Short-term High-dose Treatment with Methenamine Hippurate of Urinary Infection in Geriatric Patients with Indwelling Catheters

The urine sediment of 12 geriatric patients with indwelling catheters was quantified by the glutaraldehyde-cytocentrifuge method prior to, during and after a clinical trial of methenamine hippurate (MH), 2 g x 3 daily given for 34 days as the sole therapeutic agent for the urinary tract infection. The median leukocyte concentration in the urine of these patients was 100 cells/microliter (Q1 - Q3 50-350), i.e. tenfold higher than the upper normal limits reported in healthy probands. The median bacteriuria in the control period was 12 x 10(5) bacteria/ml urine, interquartile range 10-60 x 10(5) bacteria/ml and extreme individual values 300-500 x 10(5) bacteria/ml. Hematuria, defined as greater than or equal to 24 erythrocytes/microliter urine, was not prominent and could not be correlated with MH treatment, nor with catheter changes. The reported observations suggest that short-term high-dose treatment with MH as sole therapeutic agent reduced pyruria and bacteriuria in the group of patients studied.

Propranolol therapy in essential hypertension

Twenty-one outpatients with essential hypertension were treated with propranolol for nine weeks following a placebo period of at least two weeks. Dosage was increased from 200 mg. up to 1 Gm. per day orally, if satisfactory control of pressure was not achieved with the lower dose. Systolic and diastolic blood pressures were reduced significantly at rest as well as before and after graded exercise. However, during exercise systolic pressure only was reduced. This reduction was correlated closely with a decreased resting cardiac output; calculated total peripheral resistance increased or did not change. No changes were observed in blood chemistry which could be attributed to propranolol treatment. Cardiac failure occurred in two patients and diarrhea in one patient. Propranolol lowers blood pressure by reducing cardiac output both at rest and during exercise. There is no dose dependence above 200 mg. per day. The use of propranolol as the sole therapeutic agent should be limited to hypertensive patients with high cardiac output.

The effect of phenformin hydrochloride on serum cholesterol and triglyceride levels of the stable adult diabetic

Study of a randomly selected sample of 202 stable ketoacidosis-resistant diabetics aged 35–80 revealed that, subjects receiving phenformin hydrochloride (DBI) alone or in combination therapy had significantly lower serum cholesterol and triglyceride levels than matched diabetics treated with insulin or tolbutamide alone. A prospective study of 60 additional diabetics previously treated with diet or tolbutamide or untreated showed that phenformin as the sole therapeutic agent produced a 12 per cent fall in cholesterol, a 40 per cent fall in triglycerides, an 11 per cent fall in fasting blood sugar and a weight loss of 3 4 to 1 pound/month (average values). The average dose of phenformin was 85 mg. daily and the average period of treatment was 26 weeks. These findings were interpreted in light of current concepts of the interrelationship of disorders of carbohydrate and lipid metabolism and the mechanism of action of phenformin was considered.

An evaluation of the radiotherapeutic management of intracranial glial tumors without prior surgery.

A group of 77 patients, clinically diagnosed as having the more malignant glial tumors in which radiotherapy was the sole effective therapeutic agent, is evaluated. If the 12 patients who died within the first month and, therefore, did not complete the proposed course of therapy are excluded, the I year survival rate (24/65; 37 per cent) compares favorably with published results of patients treated with radiotherapy following partial excision.Treatment volumes in excess of 1,000 cc., or tumor doses above 4,000 rads in 5 weeks, did not alter the prognosis. Postmortem histology obtained in 46 per cent of the cases confirmed the clinical diagnosis in all but 3 instances in those patients who lived less than 12 months, and in all those patients who survived more than I year.

THE HOW, WHEN AND WHERE OF THE ORAL HYPOGLYCEMIC COMPOUNDS.

Juvenile-type diabetes is a contraindication to use of any oral hypoglycemic compound as the sole therapeutic agent. The best candidates for this therapy alone, without insulin, are diabetics whose disease appeared after the age of 40 years, is of less than 10 years' duration, and is stable, requiring small doses of insulin. Phenformin seems to enhance glucose utilization and to augment the action of endogenous or exogenous insulin; its use in obese diabetics has been recommended. In general, insulin-sulfonylurea combination therapy has not been effective. Phenformin-insulin therapy occasionally may be beneficial. A combination of sulfonylurea and phenformin also may be advantageous. Initial “loading doses” are no longer used.

EFFECT OF CHLORPHENESIN CARBAMATE (MAOLATE) ON A CASE OF ACUTE ARACHNIDISM.

Summary Following a bite on the nape of the neck by a female Latrodectus mactans, a 34-year-old Negro developed classic symptoms of acute arachnidism, including diaphoresis, nausea and vomiting, apprehension, and spasm and pain of striated muscles Intravenous injections, 15 minutes apart, each of 10 ml, of 10% calcium gluconate, induced no or only minor improvement. Chlorphenesin carbamate (Maolate®) was administered in doses of two 400-mg tablets about 1 hour after the bite and again 3 hours later. Relief occurred and the patient fell asleep; he had to be awakened for each of two additional doses. It was concluded that the drug deserves further study in arachnidism, to be used as the sole therapeutic agent.

Antifibrinolytic drug in treatment of progressive systemic sclerosis.

To the Editor: —Epsilon-aminocaproic acid (EACA), a 6-carbon amino acid which is completely excreted from the body in 5 hr, prevents the activation of the fibrinolytic system through the inhibition of the activator of plasminogen and through the direct inhibition of plasmin. 1 Plasmin is a fibrinolysin which breaks down fibrin into small polypeptides which play a part in developing the clinical manifestations of inflammation, such as diapedesis and histamine release. 2 Thirty months ago, a group of 32 patients with progressive systemic sclerosis, as diagnosed by tissue biopsy, was given EACA as the sole therapeutic agent. The patients have been treated with the following regimen: 1 week of intravenous EACA therapy totaling 210 gm of the medication in 7 days, and thereafter maintenance on 32 gm of the oral liquid preparation each day. Six patients have not shown significant reversal of symptoms during therapy. The other 22 patients have