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Biomedical subjects

S Harder

Publications and source records attributed to S Harder.

At least 73 records · Page 4Linked to original sources
PubMed1998

Novel mode of action of the calcium antagonist mibefradil (Ro 40-5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium.

Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy.

Actins↗
PubMed1998

Prescription of cardiovascular drugs in outpatient care: a survey of outpatients in a German university hospital.

AIMS: We evaluated ambulatory prescriptions by general practitioners for outpatients with cardiovascular (CV) disease referred to the cardiology outpatient clinic of the Frankfurt University Hospital in order to prove adherence to generally acknowledged therapy standards for treating CV disease. METHODS AND RESULTS: Appropriateness of current CV medication was assessed according to the following criteria: aspirin or anticoagulants obligatory after myocardial infarction (MI), unless contraindicated; beta-blockers should be prescribed after MI, unless contraindicated or not tolerated; ACE inhibitors should be given in left ventricular dysfunction (LVD) after MI, unless contraindicated; and hypertension should be adequately controlled. 346 patients (28-94 years) received a median of 3 CV drug prescriptions (range 0-7). 240 patients had CAD, 142 patients previous MI, 121 patients had LVD (59 after MI), 143 patients were hypertensive. Aspirin was used appropriately in 80% of all MI patients, 13% received oral anticoagulants due to atrial fibrillation. However, 7% received no antithrombotic therapy. ACE inhibitors were administered in 65% of the MI patients with LVD. beta-blockers were used in 25% of the MI-patients. In the remaining patients, beta-blockers were contraindicated, not tolerated, and/or verapamil had been prescribed. However, in 14% of the patients beta-blockers were withheld without evident reason or alternative drug. In 41% of the hypertensive patients, blood pressure was not sufficiently controlled. CONCLUSION: A considerable number of ambulatory prescriptions for CV drugs are not in accordance with current therapeutic guidelines. The role of a cardiology outpatient clinic to detect the misuse or underuse of CV drugs is emphasised.

Adult↗
PubMed1998

Dose response and concentration response relationship of apomorphine in patients with Parkinson's disease and end-of-dose akinesia.

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease presenting end-of-dose motor fluctuations. Aim of the study was to investigate the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuators. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) elicited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg dose, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is considered clinically relevant, a response was seen in 0/10 patients (0.5 mg), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg). The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentration vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of the individual curves averaged 20 pMol/ml. However, several curves exhibited proteresis, making the application of a PK-PD model impossible. The reason for proteresis is not clear, it might indicate acute tolerance as well as a redistribution of apomorphine from the effect site.

Adult↗
PubMed1997

Structure and activities of hospital drug committees in Germany.

OBJECTIVES: Hospital drug committees have been established to ensure rational drug use. However, with regard to their structure and duties remarkable differences between European countries may exist, reflecting the differences in drug legislation and market. Our aim was to obtain information about the structure, present activities and decision-making processes of hospital drug committees in Germany and especially the role of clinical pharmacologists in these committees. METHODS: In 1995, a questionnaire with 36 items was designed and sent to all 450 hospitals in Germany with more than 400 beds. One hundred forty three returned questionnaires were evaluated. RESULTS: According to hospital size, the median value for the annual drug budget (including the cost of blood and blood-derived products) in 1993 ranged between DM 2.4 million for hospitals with less than 500 beds and DM 30.0 million for university hospitals with more than 1,000 beds. In 53.2% of drug committees, a pharmacist holds the position of chairman, followed by medical specialists (32%); (clinical) pharmacologists hold this position in only 7.7% of the general hospitals, but in almost 50% of the university hospitals. In most cases, all clinical specialities are represented in the drug committee the number of members ranging between 5 and 40 (median 12). The number of drugs included in the internal drug list, ranging between 400 in hospitals with < 500 beds and about 700 in university hospitals, strongly correlated with the number of beds and, interestingly, with the number of drug committee members. Treatment guidelines were implemented mainly for antiinfectives (87%), infusion solutions (30%), anti-emetic drugs (5-HT3-receptor antagonists, 27%) and blood and blood-derived products such as intravenous immunoglobulins (23%). However, effective control of these guidelines was only performed in about 50% of the hospitals. A drug information service was provided in most hospitals, where 95% of queries were answered by pharmacists. CONCLUSION: The results of our survey showed that German hospital drug committees vary considerably with regard to their function and control mechanisms of drug use. Most of the responders would appreciate a more intensive exchange of current problems and treatment guidelines. Although the process of pharmacotherapeutic decision making should be supported by clinical pharmacologists, experts in this field are often not involved in German hospital drug committees.

Formularies, Hospital as Topic↗
PubMed1997

Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imidapril and digoxin in healthy volunteers.

AIMS: To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin. METHODS: AUC, Cmax and t(max) of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three-period cross-over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day(-1) + placebo (D + P); imidapril 10 mg day(-1) + placebo (I + P); imidapril 10 mg day)(-1) + digoxin 0.25 mg day(-1) (I + D). RESULTS: Mean AUC (0, 24 h) of digoxin was 10.4 (+/- 4.9 s.d.) ng ml(-1) h (D + P) and 10.7 (+/- 3.9 s.d.) ng ml(-1) h (I + D), respectively (90%-confidence intervals [CI] for the ratio of (D + P) and (I + D): 0.91-1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (+/- 86 s.d.) ng ml(-1) h (I + P) and 108 (+/- 52 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.76-0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (+/- 91 s.d.) ng ml(-1) h (I + P) and 194 (+/- 54 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.80-1.08, PE 0.93). Cmax was 19.9 (+/- 8.7 s.d.) ng ml(-1) (I + P) and 15.9 (+/- 5.3 s.d.) ng ml(-1) (I + D) (90%-CI: 0.67-1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE-inhibition was 79% (I + P) and 67% (I + D). CONCLUSIONS: Grouped data analysis of imidaprilat plasma levels vs ACE-activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml(-1). Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE-inhibition/time curves by about 20 to 30%.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Pharmacokinetics of the PDGF-antagonist trapidil in patients with and without renal impairment.

The pharmacokinetics of the PDGF-antagonist trapidil and its major metabolite desethyl-trapidil (M 1) were studied in patients with and without renal failure after a single dose of 200 mg and following 4-day treatment with 200 mg t.i.d. Twenty patients were classified according to their renal function as assessed by creatinine clearance (C(Cr)) in group A: 133.7 +/- 30.3 ml/min (n = 8), group B: 63.6 +/- 15.4 ml/min (n = 6) and group C: 17.9 +/- 6.1 ml/min (n = 6), patients on hemodialysis were not enrolled. After the first dose maximal plasma concentrations of trapidil with 5.99 +/- 1.60 (A), 5.76 +/- 1.46 (B) and 5.63 +/- 1.53 micrograms/ml (C) were not different between groups, but somewhat lower on day 4 with 4.96 +/- 0.78 (A), 5.78 +/- 1.78 (B) and 5.47 +/- 1.42 micrograms/ml (C). Similarly, AUC0-infinity-values on day 1 with 16.9 +/- 4.8 (A), 20.2 +/- 6.7 (B) and 22.2 +/- 11.2 micrograms/ml x h (C) showed only modest (NS) differences between groups, but decreased markedly on day 4 to 10.8 +/- 1.8 (A), 13.6 +/- 5.8 (B) and 14.4 +/- 4.3 micrograms/ml x h (C). Linear regression analysis between AUC and C(Cr) demonstrated no relationship between these parameters. For plasma concentrations of M 1 no significant differences were seen between groups. At steady state maximal plasma concentrations of M 1 occurred earlier and were slightly increased. In one patient (group B) receiving tamoxifen comedication markedly elevated plasma concentrations of trapidil and desethyltrapidil occurred, suggesting a pharmacokinetic interaction. Trapidil may be safely given to patients with impaired renal function, the apparent decrease of trapidil plasma concentrations may suggest autoinduction of metabolizing enzymes.

Administration, Oral↗
PubMed1997

Concentration-effect relationship of delta-9-tetrahydrocannabiol and prediction of psychotropic effects after smoking marijuana.

On the basis of a publication by Cochetto et al. [1981] we performed simulations of the effect-time course (high-rating) after smoking marijuana. The intention was to characterize the concentration-effect relationship of THC and to provide information on how long psychotropic effects (and therefore impairment of cognitive or motoric functions) last after intake of a cannabinoid product. The parameter estimates (+/-SD) of the pharmacokinetic disposition and the pharmacodynamic model (sigmoidal Emax model) after smoking 1 marijuana cigarette containing 9 mg THC were as follows: T/2 alpha = 5 minutes (+/-1.2), T/2 beta = 75 minutes (+/-23), Teq (equilibrium half-life with the effect site) = 29 minutes. (+/-2), ECe50 = 7.2 ng/ml THC (+/-0.5), E0 (baseline high rating) = 18% (+/-2.0), Emax (amplitude of the high rating) = 23% (+/-2.5), Hill coefficient = 9.0 (+/-3.0). On the basis of this curve fit, the effect-time course after repeated smoking (5 joints) in different intervals (120, 60, and 30 minutes) and for different dose strengths 9 mg (standard joint), 3 mg (weak joint) and 1 mg (agricultural hemp) were simulated. The duration of the effect after 1 dose of 9 mg is about 45 minutes. After the last cigarette, recovery (decline < 50% Emax) will last about 100 minutes. A dosing interval of 1 h leads to a continuous "high", and recovery will last about 150 minutes after the last joint. Smoking the weak dose strength (3 mg) every hour will result in a short plateau of the maximal effect (about 20 minutes) and a decline after the last joint within 1 h. Only repeated smoking every 30 minutes will lead to a prolonged plateau phase with a recovery time of about 80 minutes. Using hemp with a low THC content (1 mg), dosing intervals of 2 h and 1 h will not provoke a psychotropic response due to THC. Smoking every 30 minutes will probably lead to a short-term moderate response. In conclusion, our simulations show that dose and dosing interval are determinants of the duration of the psychotropic effects of THC. These simulations may be beneficial for the interpretation of THC levels, e.g. associated with accidents or traffic violations. Furthermore, misuse of natural hemp with a low THC content seems unlikely.

Automobile Driving↗
PubMed1996

Investigation of nifedipine absorption in different regions of the human gastrointestinal (GI) tract after simultaneous administration of 13C- and 12C-nifedipine.

OBJECTIVE: To evaluate the absorption of nifedipine in man from four different sites of the gastrointestinal tract. METHODS: On separate occasions, nifedipine solution was administered locally to the stomach, the small intestine and two sites in the colon in 4 healthy male volunteers (age 29-34 y weight 73-82 kg, non-smokers) using a remote controlled drug delivery device (HF-capsule). In order to assess absolute and relative bioavailabilities, an intravenous infusion was given on a separate occasion and all treatments were accompanied by a simultaneous oral dose of a stable-isotope labelled nifedipine solution. This allowed to minimise the influence of intra-individual variability. Plasma samples were collected up to 24 h post dose and faeces for 72 h. A new method of analysis of nifedipine in plasma and faeces using gas chromatography with mass-selective detection (GCMS) was employed. RESULTS: Dissolved nifedipine was found to enter the systemic circulation completely along the intestine, being absorbed from jejunum to colon. Absorption was less rapid from the colon than from the upper part of the gut, but this was not associated with a decrease in absorption and/or bioavailability: Absolute bioavailability, calculated from the normalised AUC values, ranged from 42 to 56%, and bioavailability relative to oral solution was 100 to 126% (medians of the application sites). CONCLUSION: The absence of an absorption window in the intestinal tract suggests that nifedipine is well suited for use in controlled-release formulations.

Adult↗
PubMed1996

Pharmacokinetics of trapidil, an antagonist of platelet derived growth factor, in healthy subjects and in patients with liver cirrhosis.

1. Pharmacokinetic parameters of trapidil (an antagonist of platelet derived growth factor) were evaluated in 12 healthy male subjects (study I) and in a group of 10 patients with liver cirrhosis (Child B) and five control subjects, respectively (study II). 2. Investigations were carried out after a single dose trapidil (200 mg) and at steady state after application of 200 mg trapidil three times daily for 5 days (study 1) or 4 days (study II). 3. Study I: The concentration-time curves of the terminal elimination phase of trapidil exhibited a slight convexity which might reflect nonlinear kinetics. The AUC of trapidil obtained after the first dose (20.5 [+/- 7.0 s.d.] micrograms ml-1 h) was markedly higher than the AUC determined at steady state (13.2 [+/- 3.8 s.d.] micrograms ml-1 h), the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.58-0.73 (point estimator 0.64). 4. Study II: AUC averaged (21.4 [+/- 9.1 s.d.] micrograms ml-1 h) in controls and (34.4 [+/- 14.9 s.d.] micrograms ml-1 h) in cirrhotic patients. The 90% confidence intervals for the difference group 1 vs group 2 was 0.95-2.97 (point estimator 1.48, P = 0.066). At steady state, AUC averaged (13.7 [+/- 5.7 s.d.] micrograms ml-1 h) in controls and (20.8 [+/- 6.8 s.d.] micrograms ml-1 h) in cirrhotic patients (90% confidence intervals group 1 vs group 2: 0.88-2.20 [point estimator 1.45, P = 0.05]). As seen in study I, the AUC of trapidil obtained after the first dose was markedly higher than the AUC determined at steady state, the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.48-0.84 (point estimator 0.66) in control subjects and 0.54-0.72 (point estimator 0.64) in cirrhotic patients, respectively. 5. An inverse correlation was seen between the results of the monoethylglycinxilidid (MEGX)-test and the AUC of trapidil (single dose: r = -0.516, P = 0.048; steady state: r = -0.548, P = 0.042). 6. Results of study I and study II indicate an autoinduction of trapidil metabolism after repeated oral doses. Although trapidil elimination is decreased in patients with liver cirrhosis (study II), the elimination half-life at steady state is relatively short (2.4 [+/- 1.1 s.d.] h) and therefore should prevent cumulation of trapidil even in cirrhotic patients.

Adult↗
PubMed1996

Clinically important drug interactions with anticoagulants. An update.

Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin.

Anticoagulants↗
PubMed1996

Criteria for the appropriate drug utilisation of immunoglobulin.

Intravenous immunoglobulins (IVIGs) are prepared from human plasma pools and further modified enzymatically or chemically. Despite careful selection of donors and inclusion of effective virus elimination steps in the production process, contamination with hepatitis C virus can still occur. IVIGs possess most of the characteristics of native immunoglobulins, such as antigen neutralisation and complement activation. The serum half-life of native immunoglobulin is about 21 days, and comparable half-lives have been reported for several IVIG preparations. IVIGs have received general approval for the treatment of primary immuno-deficiencies such as agammaglobulinaemia. Of the secondary immuno-deficiencies, only paediatric AIDS, chronic lymphocytic leukaemia and multiple myeloma, as well as allogeneic bone marrow transplantation, are accepted indications for IVIGs. Because of their immunomodulatory action, IVIGs are also recommended for the treatment of idiopathic thrombocytopenic purpura, Kawasaki disease (mucocutaneous lymph node syndrome) and, recently, Guillain Barre syndrome IVIGs have been investigated in a wide range of immunodeficient states (e.g. prematurity) and autoimmune diseases (e.g. multiple sclerosis), but conclusive results are not available. Since IVIGs are associated with a certain risk of transmission of viral infections and, secondly, because they are generally acknowledged as expensive drugs, their use requires careful consideration of risk, benefit and cost.

Animals↗
PubMed1995

Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393).

Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg.kg-1.h-1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD0-24 (APTT) came to 913 s.h.kg-1 under placebo and it was slightly increased to 1,017 s.h.kg-1 after piroxicam; the 95%- confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal Emax-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Concentration-effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

1. The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (+/- 9.1 s.d.) ng ml-1 h per mg and 23.2 (+/- 4.6 s.d.) ng ml-1 h per mg after the CR-formulation. Cmax was 1714 (+/- 1027 s.d.) ng ml-1 after the IR-formulation and 1494 (+/- 383 s.d.) ng ml-1 after the CR-formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/- 144 s.d.) ng ml-1 (IR) and 1024 (+/- 502 s.d.) ng ml-1 (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/- 0.5 s.d.) h (IR) and 2.8 (+/- 0.7 s.d.) h (CR), respectively (95%-CI: 1.12-2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Concentration-effect relationship of levodopa in patients with Parkinson's disease.

Studies on the concentration-effect relationship of levodopa in Parkinson's disease have established that: (1) in patients with a fluctuating response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e. potency is decreased) compared with those patients whose symptoms are adequately controlled; (2) with controlled-release (CR) preparations, the concentration-effect relationship indicates a decreased potency compared with conventional immediate-release (IR) preparations; and (3) coadministration of a dopamine receptor agonist (even at a subclinical dose) enhances the potency of levodopa. These findings support some current hypotheses on the origin of, and the pathophysiological process underlying, response fluctuations. In patients with response fluctuations, metabolism of levodopa and storage of dopamine in the striatum are reduced. Levodopa is decarboxylated in the extracellular space, with the result that dopamine is released directly to the effect site. Thus, without dopamine storage acting as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa concentrations. Even small fluctuations of levodopa concentrations around the EC50 value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylation of levodopa) are required. The storage buffer is responsible for a time lag between decline in peripheral plasma concentrations of levodopa and dopamine-induced motor response. Low doses of a dopamine receptor agonist increase the basal tonus of the striatum, but do not reach the threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switch from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-pharmacodynamic modelling does not give a clear answer as to whether response fluctuations are additionally induced by receptor desensitisation or inhibition of the active transport of levodopa across the blood-brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Nevertheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations are compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response fluctuations. The interindividual variability of EC50 values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical effects). However, considering the short elimination half-life of levodopa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interval with CR preparations might be limited by the higher threshold concentrations of levodopa necessary to maintain clinical effects.

Antiparkinson Agents↗
PubMed1995

Absorption behavior of sulpiride described using Weibull functions.

Deconvolution absorption profiles of oral sulpiride formulations were calculated from plasma concentration-time data obtained in an open, 3-period study with a crossover of the 2 oral formulations in 12 healthy volunteers following single intravenous (100 mg) and oral (2 x 50 mg capsules, 200 mg tablets) application of sulpiride. A model based on 2 Weibull-functions, and applied using NONMEM, described the complex absorption profiles more satisfactorily than a first order absorption model or a model based on a single Weibull-function.

Absorption↗