Thoracic idiopathic spinal cord herniation in a young patient: a diagnostic and therapeutic challenge.

Idiopathic Spinal Cord Herniation (ISCH) is considered to be a rare cause of Thoracic Myelopathy. It is secondary to the gliding of the Spinal Cord through an anterior dural defect, without a completely defined cause. We present a case of ISCH which, even though was in its usual location, developed in a woman at a younger age than expected. The patient was 20 years old when diagnosed with Brown-Séquard Syndrome. MRI showed herniation at T4-T5 level, which was corrected using a posterior approach to expose the dural defect, reduce the herniation and place a heterologous graft. Postoperatively, neurological function improved, and adequate reduction was seen on imaging. Given the reports of recurrence and deterioration that have been seen after 18 months, follow-up was prolonged for a total of 2 years. We consider postoperative MRI performance important to establish the degree of reduction and alignment of the Spinal Cord.

Selegiline in the treatment of Parkinson's disease--long term experience.

L-deprenyl (selegiline) has been reported as a safe effective adjunctive agent to levodopa in the control of Parkinson's symptoms, as well as a means of preventing the progressive nature of the disease process. In an ongoing study, now in its 12th year, L-deprenyl has been administered 1. as monotherapy or 2. in combination with levodopa, to previously untreated patients in the early phases of the disease; 3. added to an existing regimen of levodopa when optimal therapeutic results are not being obtained. This report reviews our experience in each of these three treatment categories. Results obtained to date, indicate that L-deprenyl administered alone does not prevent the occurrence of signs of Parkinson's disease. Its administration with levodopa, as initial therapy, allows for use of lower dosage and less side-effects of the latter agent. When L-deprenyl is added to sub-optimal responders to levodopa, it attenuates fluctuating responses, particularly those of the 'end-of-dose' variety.

Treatment of Parkinson's disease in early and late phases. Use of pharmacological agents with special reference to deprenyl (selegiline).

There are at present numerous pharmacological agents available for the control of parkinson symptoms. None are ideal; all have their limitations. The most potent is levodopa administered with a peripheral decarboxylase inhibitor. However, because its effectiveness declines after long-term use and side effects increase in severity, it should be reserved for individuals with established symptoms which are functionally impairing. In patients with minimal symptoms, anticholinergic agents, or agents which facilitate dopaminergic mechanisms normally operative in the nervous system, should be used. In a limited trial, deprenyl has produced promising results during this phase of parkinsonism. Deprenyl's major usefulness however, has been demonstrated in patients under treatment with levodopa which has become complicated by fluctuating responses--particularly those of the end-start-dose variety. In such patients, it is possible to achieve an increase in "on" time and a decrease in the severity of parkinsonism. In most patients, such a response can maintained for a period of two years or longer.

A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine.

BACKGROUND AND OBJECTIVES: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. METHODS: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. RESULTS: A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. CONCLUSION: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

Early combination of selegiline and low-dose levodopa as initial symptomatic therapy in Parkinson's disease. Experience in 26 patients receiving combined therapy for 26 months.

Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age, 57.3 years; mean Parkinson's disease duration, 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage, 2; mean motor scores, 11.4) were given selegiline (Deprenyl), 10 mg daily, and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet, 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy, seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa, with significant decreases in their rated motor scores, such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%, compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose, 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild, transient, abnormal involuntary movements, and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Selegiline use to prevent progression of Parkinson's disease. Experience in 22 de novo patients.

To test the hypothesis that selegiline (L-deprenyl), a selective inhibitor of B-type monoamine oxidase, can halt the natural progression of Parkinson's disease, its use in 22 naive patients (mean age, 58 years; mean Parkinson's disease duration, 2.3 years) in the early stages (1 to 2) of the disease was studied. Patients were started and maintained on a daily dose of 10 mg of selegiline, and they underwent neurologic examinations at 3-month intervals using our center's disease staging and total rated disability scores. The criterion set for disease progression was defined as either the appearance of a new objective sign and/or a definite, persistent worsening (greater than 25%) of existing signs after the initiation of the selegiline trial. Patients remained on a regimen of selegiline [corrected] for periods ranging from 7 to 84 months. At the time of their latest neurologic examination, 17 (77%) of the 22 patients had conditions that demonstrably worsened with selegiline alone at an average of 10.8 months from the start of the drug therapy. Six of these 17 patients with worsening conditions (or 27% of the original 22) eventually required the addition of levodopa with carbidopa (Sinemet) on average at 13 months from the start of selegiline therapy; they have continued, to date, taking this combination for an additional mean follow-up period of 20.7 months. Four of the original 22 patients had relatively unchanged, stable neurologic status at the time of their latest examination (average follow-up period, 11.6 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Selegiline as an adjunct to conventional levodopa therapy in Parkinson's disease. Experience with this type B monoamine oxidase inhibitor in 200 patients.

Two hundred patients at a median age of 63 years, receiving conventional levodopa therapy for 8 years, who had had Parkinson's disease for 10 years, tried a regimen of selegiline (L-deprenyl), a type B monoamine oxidase inhibitor, at a daily dose of 10 mg, for varying periods from less than 6 months to more than 24 months (28% over 24 months). Selegiline does improve parkinsonism during the initial 6 months to 12 to 24 months of combined therapy in one third to almost half of patients with an end-of-dose type of response to long-term levodopa therapy. However, even this particular class of patients is unable to maintain such an improvement by 36 months, much less by 48 months, from the start of the selegiline trial. About one quarter of poor responders to levodopa and those with random deterioration show improvement in their parkinsonian status in the first 6 months of the selegiline trial, but their conditions quickly deteriorate by 1 year. The predominant pattern of response to previous levodopa therapy and the severity of the total disability score at the initiation of the selegiline trial were the two variables that were predictive of risk of failure with the drug. No evidence suggested that selegiline decreases the excess mortality rate of Parkinson's disease above that achieved with the use of levodopa alone. Selegiline as an adjunctive agent to conventional levodopa therapy was not unduly impressive with regard to preventing progression of Parkinson's disease.

Impact of an antibiotic restriction policy on hospital expenditures and bacterial susceptibilities: a lesson from a pediatric institution in a developing country.

BACKGROUND: In an era of growing concern about bacterial resistance and hospital costs, limiting the use of broad spectrum antibiotics is important. OBJECTIVES: To evaluate the effects of an antibiotic restriction policy on expenditures, antimicrobial resistance rates and clinical outcomes of hospitalized children. DESIGN: Starting in January, 1997, a prior consultation with an infectious disease specialist for using restricted antibiotics was required in all hospital areas. A retrospective assessment of study objectives obtained 2 years before (1995, 1996) and 2 years after (1997, 1998) initiation of the restriction policy was performed. SETTING: The present study was conducted in a 500-bed university hospital serving children nationwide of a developing country, Panama. RESULTS: Total expenditures for antimicrobial agents decreased by 50%, from $699,543 (US dollars) during 1995 and 1996 to $347,261 during 1997 and 1998. Susceptibility rates of many nosocomial isolates (especially staphylococci and Gram-negative enteric bacilli) usually improved for restricted antibiotics with >35% reduction in utilization (notably for gentamicin, third generation cephalosporins, piperacillin and vancomycin). Major improvements in bacterial susceptibilities were observed in the nursery, a place harboring microorganisms exhibiting the higher initial resistance rates of the hospital. No differences in days of hospital stay and mortality rates of all patients and of children with nosocomial infections were detected during the study period. CONCLUSIONS: Requirement for prior approval of selected antimicrobial drugs in a pediatric institution decreases hospital expenditures and improves susceptibilities to antibiotics without compromising patient outcomes or length of hospital stays.

Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin.

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of "switching," an individual bioequivalence study involving a replicate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product. A randomized, single-center, open-label, single-dose, four-way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine.

While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Movement disorders in the psychiatric patient.

Abnormal movements or postures often present a diagnostic and therapeutic challenge to the psychiatrist or neurologist. The authors review pertinent anatomy and physiology of disorders of the extrapyramidal system, suggest aspects of the clinical history and examination particularly important for diagnosis, and describe a range of abnormal movements. They review several syndromes in which abnormalities of behavior and movement may occur together, including Huntington's chorea, Wilson's disease, Parkinson's disease, and tardive dyskinesia.

Chronic illness and the physician-patient relationship: a response to the Hastings Center's "ethical challenges of chronic illness".

The following article is a response to the position paper of the Hastings Center, "Ethical Challenges of Chronic Illness", a product of their three year project on Ethics and Chronic Care. The authors of this paper, three prominent bioethicists, Daniel Callahan, Arthur Caplan, and Bruce Jennings, argue that there should be a different ethic for acute and chronic care. In pressing this distinction they provide philosophical grounds for limiting medical care for the elderly and chronically ill. We give a critical survey of their position and reject it as well as any attempt to characterize the physician-patient relationship as a commercial contract. We emphasize, as central features of good medical practice, a commitment to be the patient's agent and a determination to acquire and be guided by knowledge. These commitments may sometimes conflict with efforts to have the physician serve as an instrument of social and economic policies limiting medical care.

Criteria to assess in vivo performance and bioequivalence of generic controlled-release formulations of carbamazepine.

PURPOSE: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of Cmax, respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve. METHODS: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. RESULTS: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters. CONCLUSIONS: The additional parameters examined may supplement the traditional single-point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Human transplacental transfer of carbidopa/levodopa.

A paucity of information is available concerning the use of levodopa and carbidopa during pregnancy. Particularly lacking is whether these agents cross the placenta and whether levodopa undergoes metabolism in the fetus. The present study carried out in aborted fetal tissues demonstrates that levodopa crosses the placental barrier and suggests that it may be metabolized in fetal tissues, including the brain and spinal cord. The possibility exists that early exposure to levodopa or dopamine may alter the normal neuronal development in the fetus, and caution in the use of levodopa during pregnancy should be observed.