Double-blind Clinical Studies Research Articles

Overview of Clinical Experience with Pefloxacin in Uncomplicated Cystitis

Pefloxacin is highly active in vitro against the organisms commonly isolated from patients with uncomplicated lower urinary tract infection. After administration of a single oral dose of 800mg, high urinary concentrations of unchanged pefloxacin and N-demethylpefloxacin (norfloxacin) are maintained for up to 168 hours (7 days). Thus, the urinary concentration of pefloxacin remains above pefloxacin MIC90 values against the majority of common urinary tract pathogens for more than 5 days postdose. Data from open comparative or noncomparative, and double-blind comparative clinical studies confirm the clinical and bacteriological efficacy of a single oral dose of pefloxacin 800mg in acute cystitis, with cure rates ranging from 80 to 97% and 79 to 96%, respectively.

Somatostatin analogues and pancreatic fistulas.

Consideration is given to the characterisation of pancreatic fistulas (PFs), the rationale for their treatment, and supportive and specific treatment measures. Choice of treatment should be based not only on the percentage of closures achieved, but also on their time and cost. The combined use of parenteral nutrition (TPN) and somatostatin inhibits pancreatic secretion well; no therapy can inhibit it completely. Presumptive use of octreotide, a subcutaneous formulation of somatostatin, in patients undergoing elective pancreatic surgery, reduced postoperative complications, mainly PFs, in about 500 patients in two controlled double-blind clinical studies, confirming the use of octreotide both in prophylaxis and treatment. Octreotide has been tested on out-patients after a brief hospitalisation period, at a dose of 100 mg three times a day. Home treatment does not involve co-administration of TPN, thus lowering not only costs but also risks. Optimal doses and the types of fistula amenable to this therapy need to be established and we only use out-patient treatment for chronic low-output fistulas.

Psychopharmacology in Child and Adolescent Psychiatry: A Review of the Past Seven Years. Part I

To present a critical overview of the literature published in the past 7 years on the efficacy and safety of psychoactive agents in mental retardation with associated psychiatric disorders, autistic disorder, Tourett's disorder, and attention-deficit/hyperactivity disorder. Double-blind and placebo-controlled clinical trials and open studies were reviewed and selected reports presented. The literature review reveals that progress has been made in the psychopharmacological treatment of the above conditions. This is partly because more studies use larger sample sizes and a narrower age range of diagnostically homogeneous patients and use a more sophisticated methodology than in previous years. Greater attention is being paid to a critical assessment of psychoactive agents and to their safety, to the efficacy as well as to the effectiveness of drugs. The 5-year National Plan for Research on Child and Adolescent Mental Disorders (1991) based on the Institute of Medicine Report (1989) already has had a significant impact on psychophamacology research. Advances in methodology, initiatives of the National Institute of Mental Health, and the advent of DSM-IV should continue to enhance research and improve pharmacotherapy in clinical practice.

Clinical utility and safety profile of iomeprol

Iomeprol is a new triiodinated, nonionic radiographic contrast agent prepared for injection at a number of concentrations (150, 200, 250, 300, 350 and 400 mgI/ml), each of which has osmolality and viscosity properties that are more favourable than other current nonionic monomers at the same iodine concentrations. Pharmaco-toxicological studies in animals have demonstrated that the molecular toxicity of iomeprol is very low. Intensive monitoring of vital, electro-physiological, and biochemical parameters in clinical studies have shown that iomeprol does not have clinically significant effects on the more important body systems and functions. Out of 7799 patients to whom iomeprol was administered, adverse events were observed in only 437 (5.6%). Of these events, the majority were rated as mild. In double-blind controlled clinical studies the contrast efficacy of iomeprol was shown to be as good as that of reference contrast media. The good efficacy was confirmed in a very large number of uncontrolled studies.

Double-Blind Study of the Safety, Tolerance, and Diagnostic Efficacy of Iopromide as Compared with Iopamidol and Iohexol in Patients Requiring Aortography and Visceral Angiography

Nonionic contrast media have been shown to be more effective, better tolerated, and safer than standard high-osmolality contrast media when given intravascularly. The aim of this study was to assess the diagnostic efficacy, tolerance, and safety of a new nonionic contrast agent, iopromide (370 mg I/mL), in comparison with two available similar agents, iopamidol (370 mg I/mL) and iohexol (350 mg I/mL), in two randomized, double-blind clinical studies of patients undergoing abdominal aortography and visceral angiography. The iopromide group included 80 patients, and the comparator group consisted of 36 iopamidol and 45 iohexol patients. The quality and diagnostic efficacy of all three contrast agents was rated equally as either good or excellent. On a scale of 0 (none) to 3 (severe) for heat and pain, respectively, the mean scores were 1.08 and 0.43 for iopromide in comparison with 1.15 and 0.35 for the comparator media. Minor adverse clinical experiences were noted in 23% of the iopromide group versus 20% of the comparator group. Nausea and vomiting were more common in the comparator group (7% versus 3%), and headache was noted only in the iopromide group (4%). There were no clinically significant changes in laboratory values in any group. Three severe adverse experiences occurred, but all were deemed unrelated to the contrast agents. Based on the results of this study, iopromide appears to be efficacious, safe, well tolerated, and comparable with iohexol and iopamidol for use in abdominal aortography and visceral angiography.

The Role of Nucleotides in Adult Nutrition

AbstractDietary nucleotides, found in normal diets, have been recently determined to be required for normal immune defenses. Rejection of cardiac transplants, graft-vs.-host disease, and delayed cutaneous hypersensitivity in animal models are all suppressed by a diet deficient in nucleotides. T lymphocytes seem to require dietary nucleotides for normal maturation and function. Host resistance to bacterial and fungal infections is decreased in mice on nucleotide free diets; addition of RNA or uracil prevents this vulnerability to infection. Dietary RNA is required to restore lost immune function after protein deprivation. Adequate calories and protein alone do not return immune function to normal. Dietary nucleotides can restore lost immune function even during protein starvation and weight loss. Because all parenteral and most enteral nutrient solutions are nucleotide free, clinical studies were undertaken comparing a new nucleotide containing diet (Impact) to a standard high protein enteral feeding. In two separate double blind clinical studies the patients fed the enteral diet containing nucleotides had improved immune function compared with patients receiving a nucleotide free diet. In addition, infectious complications and length of hospital stay were reduced in postoperative cancer patients fed Impact compared with a control group.

Angiotensin-Converting Enzyme Inhibition and Renal Protection

The role of hypertension in the pathogenesis of renal damage is a subject of both historical interest and current investigation. Because of the difficulty associated with studying the pathophysiologic role of glomerular injury in systemic hypertension, experimental models have provided much of the data in this field. The mechanisms leading to glomerular injury are complex and not fully elucidated. Mesangial and endothelial cell injury are thought to be important pathophysiologic mechanisms in the renal injury associated with hypertension. One hypothesis suggests that glomerular hypertension (ie, a hemodynamic event) is the primary pathogenetic mechanism, but another supports the notion that glomerular hypertrophy (ie, abnormal growth-related events) contributes to injury. The intrarenal renin-angiotensin system may play an important pathogenetic role in end-stage renal disease. Angiotensin-converting enzyme (ACE) inhibition has been shown to arrest the progression of renal injury in animal models. Although the clinical database is incomplete, the findings of anecdotal reports and short-term studies suggest that ACE inhibition may preserve renal function in patients with scleroderma renal crisis, reduce proteinuria in patients with diabetic nephropathy, and normalize renal hemodynamics in patients with a variety of renal diseases. The beneficial effects of ACE inhibition may be due to both hemodynamic (eg, reduction in glomerular capillary and intraglomerular pressures) and nonhemodynamic (eg, potassium-sparing and reduction in mesangial proliferation) mechanisms. The precise role of ACE inhibitors in the prevention of renal damage awaits the results of ongoing long-term, double-blind clinical studies. Nevertheless, ACE inhibition may be an appropriate therapeutic alternative in the hypertensive patient whose renal injury is progressing despite aggressive antihypertensive therapy.

Past and current clinical studies with GM-1 ganglioside in acute spinal cord injury

Two recent prospective, randomized, placebo-controlled, double-blinded clinical drug studies in acute spinal cord injury have reported enhancement of neurologic recovery of motor function. The drugs investigated in these studies were methylprednisolone and GM-1 ganglioside. Before these studies, the treatment of patients with spinal cord injuries had been restricted to prevention of further injury to the spinal cord, limiting secondary damage following the initial injury, increasing the patient's ability to function through intensive rehabilitation, and facilitating any spontaneous recovery of neurologic function. Methylprednisolone is a steroid administered at very high levels, and GM-1 is a complex acidic glycolipid found at high levels in cell membranes in the mammalian central nervous system with known neuroprotective and neurofunctional restoration potential. This article summarizes the previously reported Maryland GM-1 clinical trial and presents the clinical and statistical design of a larger clinical trial being conducted with the purpose of verifying a beneficial GM-1 drug effect when administered with methylprednisolone in acute spinal cord injury.

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients wtth mild to moderate uncomplicated essential hypertension. After a 3–6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9,9.3,9.2,111, and 13.2 mm Hg hi the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p <0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p <0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p <0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.

Analysis of advancing age on the response to nicardipine among 467 adult hypertensive patients

The antihypertensive response to nicardipine was analyzed in 467 hypertensive patients who had participated in four similarly designed double-blind clinical studies in which the effectiveness of nicardipine was evaluated. This population was divided into five age groups. The difference in response rates between the youngest (less than or equal to 39 years) and oldest group (greater than or equal to 70 years) of patients was less than 5%. After 12 weeks of treatment with nicardipine, the rate of response for each decade ranged from 65% to 77%. The per cent decrease in blood pressure was not age dependent, but did correlate with the pretreatment systolic and diastolic blood pressure (P less than 0.001). No age-related trend in side effects was observed. The incidence of side effects ranged between 0% among the oldest patients to 17.3% in patients 50-59 years of age. No adverse metabolic effects were found in any age groups. These results indicate that nicardipine, a calcium entry-blocker, is effective and useful in adult hypertensive patients of all ages.

5-HT-related drugs and human experimental anxiety

Clinical observations and double-blind studies demonstrated an anxiolytic effect of drugs that facilitate serotonergic transmission on several anxiety disorders. There is a latency of several weeks for their anxiolytic effect to take place. There may be, in addition, a biphasic effect, i.e., an acute anxiogenic effect followed by an anxiolytic effect after chronic use. In addition, acute administration of m-chlorophenylpiperazine (MCPP), an agonist of 5-HT-1 receptors, increased anxiety in normal volunteers as well as in patients with panic or obsessive-compulsive disorders. Studies in health volunteers have been performed in our laboratory to explore the acute effect on human anxiety of drugs that selectively influence 5-HT neurotransmission. We observed that acute administration of chlorimipramine enhanced the rise in anxiety induced in healthy volunteers by speaking in front of a video camera. With a similar experimental design, we also demonstrated an anxiogenic effect of metergoline, a nonselective 5-HT receptor blocker. It is suggested that the proanxiogenic effect of acute administration of 5-HT uptake inhibitors may be due to impaired 5-HT neurotransmission.

Electrical Stimulation Applied to Bone and Nerve Injuries in the Upper Extremity

In conclusion, electrical stimulation of bone has advanced from the laboratory to clinical reality. Despite the lack of good double-blind clinical studies, it is impossible to ignore the excellent results reported from numerous multicenter trials. Doubts and controversies will and should continue. Electrical stimulation has a definite place in the treatment of scaphoid nonunion as well as other failures of osteogenic biology in the upper extremity. The future may realize the enormous potential of electrical stimulation in areas of nerve repair, wound healings, or osteoporosis. The hand surgeon may soon be operating in the age of biophysics where he or she can charge by the kilowatt hour. Yet one should not become a mere technician, but understand the basic science of what one is doing and, above all, maintain a balanced and critical approach.

Use of budesonide in the treatment of pulmonary sarcoidosis.

Twenty patients with active sarcoidosis (increased serum ACE activity) and progressive pulmonary disease (stages 2-3) were treated with inhaled budesonide instead of with oral glucocorticosteroids in an open clinical study. Results after an 18-month treatment are reported. A general improvement in chest roentgenograms and FVC was noted. Serum ACE activity was normalized. The results indicate that pulmonary manifestations of sarcoidosis can be treated with the inhaled steroid, budesonide. In this way the risk of systemic side effects is considerably reduced. The final place of inhaled budesonide in the treatment of sarcoidosis must be determined via placebo-controlled and comparative, double-blinded clinical studies in larger series of patients.

The Social and Psychological Origins of the Climacteric Syndrome.

The social and psychological origins of the climacteric syndrome. John G. Greene. Gower Publishing Company Ltd., Aldershot, U.K. and Brookfield, VT, 1984, 247 pp., $ 29.50. When I first became involved in research on the psychosocial aspects of the climacteric in 1969 I had only few studies to refer to. Only the study by Neugarten and coworkers (1963) and the study of Laszlo Jaszmann (1967) into the epidemiology of climacteric complaints, a study in which I had been indirectly involved, gave me some clues about the importance of social factors for symptom formation in the years around the menopause. Uninhibited therefore by too much knowledge, and largely ignorant about sociological techniques, I leapt into my first research project: a comparative study of attitudes towards the menopause in five European countries. When the results appeared I had progressed in my thinking, and guided by Jean Kellerhals, a sociologist who joined forces with me, we continued our expeditions into that unknown area: the climacteric as a psychosocial and cultural phenomenon. Now, fifteen years later, climacteric research has come of age. I am grateful to John Greene for having compiled this status quo report of work done in the past. The first chapters of this book, on terminology, on climacteric symptoms and oestrogen therapy are primarily intended, I think, to explain to the social scientist what the climacteric means in medical terms. Still, they are a useful introduction even for the medical researchers in this field. I was surprised to see how few good placebo-controlled, double-blind studies have been done into the effects of oestrogens on climacteric complaints. The author has reviewed these critically. With regard to effects of oestrogens on the psyche, the author concluded: “any psychotropic effect of oestrogen remains undemonstrated”. I tend to agree with that statement. Controlled studies have provided insufficient evidence for any such effect. Yet every clinician who has treated climacteric patients has been struck by the consistency in the effect of oestrogen therapy on psychic well-being of his patient. Obviously it is difficult to quantify such an effect, but I am sure that, in time, the evidence will be brought forward. Not only are well-controlled, double-blind clinical studies on the effect of therapy few in number, but also studies of the social, cultural and psychological factors influencing symptom formation at the climacteric are scarce. The advantage however, is that here the research done by different workers is often complementary, each study adding a piece or several pieces to the jigsaw puzzle. This book shows the jigsaw puzzle as it is today. The author has incorporated new ideas and findings concerning the effects of life events such as death in the natal family into the concept that has grown over the years. He comes to a synthesis and presents a model of vulnerability which is very attractive and allows us to identify which women are heading for a difficult climactaric and which are not. The

Renal handling and acute urinary electrolyte effects of aminoglycoside antibiotics: Use of a solitary renal autotransplant in the conscious sheep

Renal handling of the aminoglycoside antibiotics gentamicin and tobramycin were studied before and after one hour of constant intravenous infusions adjusted to maintain a concentration of 15 μg/mL. A solitary renal autotransplant model in four conscious volume replete 40 Kg sheep was used. This unique surgical preparation allows sampling of renal arterial and renal venous blood as well as urine drained through an exteriorized parotid-ureteral fistula. This surgical preparation has considerable potential in renal pharmacology since it uses a conscious, large animal. Baseline studies in this preparation demonstrated normal, 51CrEDTA and 125I PAH, clearances which were unaffected by the drugs. Aminoglycoside binding to pooled sheep sera was 11% at physiologic PH. calcium and magnesium concentrations. A–V difference was 1.3 ± .3 μg/mL and extraction by the kidney was 9 ± 3.2% with no differences between gentamicin and tobramycin. Clearance of gentamicin was 84% and tobramycin 86% of GFR. There was no evidence of tubular injury as evidenced by unchanged urinary beta-2 microglobulin excretion. Serum Na, K, Ca and Mg did not change over the course of the study. Both drugs caused a prompt decrease in absolute and fractional sodium excretion while only gentamicin produced a kaliuresis. Early aminoglycoside effects on electrolyte balance may be an eventual determinant of nephrotoxic potential rather than differences in renal drug handling. Nephrotoxicity is a major side effect of aminoglycoside antibiotic therapy. Although gentamicin and tobramycin have similar pharmacokinetics, including renal cortical accumulation, both double blind clinical studies (1) and experimental data (2) have shown that gentamicin is more frequently associated with renal dysfunction. Recent studies in the dog have suggested that hypokalemia due to renal potassium wasting is a risk factor predisposing to nephrotoxicity (3). In clinical usage aminoglycosides may induce hypokalemia and hypocalcemia, perhaps resulting from drug-induced magnesium depletion (4). Previous studies reporting data concerning the acute effects of aminoglycosides on renal function and electrolyte excretion have used anesthetized animals (5) or isolated perfused kidney preparations (6). The present experiments utilize a unique surgical preparation in which a solitary kidney is autotransplanted to the neck of a sheep followed by a contral ateral nephrectomy. Urine flow is exteriorized through a uretero-parotid-cutaneous fistula thus providing a conscious animal with ready access to renal arterial and renal venous blood. Our results show that renal handling of gentamicin and tobramycin do not differ during short-term constant infusions. Both drugs caused a decrease in sodium excretion while gentamicin caused a larger increase in fractional and absolute potassium excretion. This raises the possibility that nephrotoxic properties of aminoglycosides may be secondary to their effects on electrolytes.

Buspirone: An anxioselective alternative for the management of anxiety disorders

1. 1. Buspirone HCl (Buspar tm ) is a novel anxiolytic agent unrelated to the benzodiazepines or other psychotherapeutic agents. 2. 2. Animal studies support an anxioselective profile, i.e. relief of anxiety without sedation, muscle relaxation or anticonvulsant activity. 3. 3. Double-blind clinical studies show buspirone to be effective in the treatment of anxiety and anxiety in the presence of depression. 4. 4. The effects of buspirone on psychomotor function, physical dependence and abuse potential tests are similar to those seen with placebo treatments. 5. 5. Mechanism of action studies indicate activity in a variety of neuronal systems.

A new orthomolecular protocol for treating multiple sclerosis and related diseases

Because of a defective gene in the human gene pool and the poor and inadequate correction of the resulting potentially-fatal birth defect, Hypoascorbemia, all multiple sclerosis (MS) patients, as well as victims of other ailments, are a scorbutic population suffering from two diseases, the second disease being chronic subclinical scurvy (the CSS Syndrome). Recent work has added support to the hypothesis that MS is a viral infection of the central nervous system (CNS). It is known that the elimination of the chronic subclinical scurvy in patients afflicted with a wide spectrum of serious viral infections, using daily megadoses of ascorbate in the range of about 100 to 300 grams, provides rapid relief of the viral disease. It is proposed that double-blind clinical studies be conducted on a non-scorbutic population of MS victims, using a protocol which eliminates their chronic subclinical scurvy with the proper daily “mega” intakes of ascorbate.

The neuroleptically active isomer of clopenthixol. A presentation of five double-blind clinical investigations and other studies with cis(Z)-clopenthixol (Cisordinol�, Clopixol�)

The neuroleptically active isomer of clopenthixol. A presentation of five double-blind clinical investigations and other studies with cis(Z)-clopenthixol (Cisordinol�, Clopixol�)

Pharmacological challenges to the endogenous opioid system in affective illness.

The discovery of an endogenous opioid system has been rapidly followed by animal studies suggesting its importance in neuroendocrine regulation and behavior. Abnormalities of these functions in affective illness suggest that evaluation of behavioral and hormonal responses following the clinical administration of opiate agonists or antagonists might yield information pertinent to the pathogenesis, diagnosis, and treatment of depression. However, initial double-blind controlled clinical studies have yielded little evidence to support this suggested involvement of the opioid system in affective illness. Acute administration of opiate agonists has sometimes yielded a mild antidepressant response in depression, and naloxone has occasionally been reported beneficial in mania. There is, however, little to suggest that these responses are specific to affective illness. A decreased prolactin response to morphine administration has been reported in depression, but is not direct evidence of opioid system dysfunction in depression since abnormal prolactin responses to other challenges in depression have previously been reported. The endogenous opioid system is actually multiple systems marked by distinct distributions of multiple endogenous opioid peptides and opiate receptor subtypes, as well as varying accessibility to drug administration. Future challenges in depression may rely upon the development of opiate agonists and antagonists with preferential binding to opiate receptor subtypes and preferential distributions to stress particular endogenous opioid systems. Opiate peptide challenges may well be administered intrathecally to overcome the blood-brain barrier. Opiate antagonist challenges will rely upon increasing doses of naloxone, up to 10 mg/kg, in order to increase the range of blocked endogenous opiate systems. Chronic administration of challenges has been a seldom used strategy but may be important in evaluation of the physiology of sensitization and tolerance to pleasure in affective illness.

A critical evaluation of treatment of calcium stones.

Although various treatment programs have been introduced for the medical management of calcium urolithiasis, their therapeutic efficacy has been difficult to appraise critically, because of failure to define clearly indications for treatment, limited double-blind clinical trials and over-reliance on retrospective stone history. However, recent progress concerning pathogenesis of stone formation has provided an improved understanding of mechanism of drug action, and of indications for treatment. Moreover, some objective data have been gathered supporting clinical efficacy of certain treatment regimens, despite continued problems in initiation of controlled (double-blind) clinical studies.