Chiropractic patients in the Netherlands: a descriptive study.

BACKGROUND: Despite the worldwide popularity of chiropractic, there is still relatively little known about the patients who visit chiropractors in the Netherlands and other European countries. OBJECTIVE: To describe in-depth the patient population of new patients to chiropractors in the Netherlands. DESIGN: Study population consisted of 10 consecutive new patients per participating chiropractor. A retrospective-type questionnaire was used. SETTING: Private practice. OUTCOME MEASURES: Mode of referral, area, and nature of the complaints; related to the chief complaint: previous treatments, examinations, type of referral, days lost at work, level of pain, and treatment expectations. RESULTS: Of the 130 chiropractors registered with the Netherlands Chiropractors'Association, 94 chiropractors(78%) participated. Eight hundred thirty-three patients (89%) returned questionnaires. By far, the greatest reason that patients visit chiropractors in the Netherlands is for neuromusculoskeletal (NMS) complaints. At the time of examination, 86% of the patients had spinal-related complaints, of which 12% involved multiple areas of the spine. Non-NMS complaints are minimal (<2%). Seventy-seven percent of patients with NMS complaints have chronic complaints (>12 weeks). Three-quarters of these patients have undergone previous conservative therapy for their complaint, which includes physical and manual therapy, postural correction, and exercise therapy. Despite the chronic nature of their complaints, patients have high expectations that their treatment will be effective. CONCLUSIONS: Most patients who see chiropractors in the Netherlands have chronic NMS-related complaints. Chiropractors are not a part of the normal referral system in this country, with the result that the patients have rather long histories, including previous evaluations by medical specialists and other previous forms of (conservative) care.

Chiropractic in The Netherlands: a survey of Dutch chiropractors.

BACKGROUND: In the Netherlands, there is increasing public and political interest in chiropractic treatment. There is, however, very little descriptive information available in the Netherlands on the chiropractic profession. Therefore, a survey was conducted among all Dutch chiropractors. METHODS: A questionnaire was sent to all members of the Netherlands' Chiropractors Association (n = 59). It contained questions on (postgraduate) education, practice management, diagnostics (including radiology use), treatment, interprofessional cooperation and referral. RESULTS: The response was 88%. Chiropractic is growing rapidly: the number of chiropractors has doubled in five years. Chiropractors primarily treat back and neck pain, with an average of 8 treatments. Conventional orthopedic and neurological examination along with motion palpation are the cornerstones of physical examination. The respondents stressed the importance of direct access to radiography and specialized (hospital) diagnostics. Fifty-eight percent of the chiropractors have their own X-ray equipment. The most frequent reason for taking new X-rays was the absence of cooperation with radiology departments. Self-referral is the largest source of patients. The referral rate to other health care professionals is low. CONCLUSIONS: The number of chiropractors is growing rapidly. They have an exceptional position in the Dutch health care system. Access to X-ray and more specialized diagnostics are presently the most important political issues.

Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethyldithiocarbamate or atomic absorption spectroscopy.

The pharmacokinetics of the cisplatin (DDP) species detected by measurement of diethyldithiocarbamate (DDTC)-reactive species (DDTC-DDP) were compared to the pharmacokinetics of the species detected by measurement of total ultrafilterable platinum in patients receiving DDP alone or in combination with the nephroprotective agent sodium thiosulfate. The doses of DDP studied were 100 mg/m2 (11 courses given to eight patients) and 202.5 mg/m2 (five courses given to four patients) given as 2 h i.v. infusions, the latter with concurrent thiosulfate. When DDP was given alone (100 mg/m2) the two assays yielded the same area under the curve (AUC) values for DDTC-DDP and total ultrafilterable platinum during the first 4 h after the start of infusion; however, beyond 4 h post-infusion, the AUC for total ultrafilterable platinum was consistently greater than that for DDTC-DDP. When DDP was given with thiosulfate (202.5 mg/m2), the AUC for total ultrafilterable platinum was significantly greater than that of DDTC-DDP during the whole sampling period. The ratio of the AUC for total ultrafilterable platinum to DDTC-DDP, when DDP was given with thiosulfate, was barely significantly greater than that when DDP was given alone. These data indicate that during and immediately following a short infusion of DDP the major platinum-containing species present in plasma ultrafiltrate are still capable of reacting with nucleophilic sites on molecules such as DDTC; however, as the reactive species are eliminated, longer half-lived non-reactive ultrafilterable platinum species begin to predominate. They also indicate that although thiosulfate does neutralize a measurable amount of DDP in the plasma on the schedule employed, this degree of neutralization is not sufficient to explain the protection against DDP-induced nephrotoxicity produced by thiosulfate.

Uridine pharmacokinetics in cancer patients.

The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-L-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57 +/- 0.28 and 1.79 +/- 0.62 min and a terminal half-life of 17.5 +/- 7.3 min. The volume of distribution was 481 +/- 70 ml/kg, and the plasma uridine clearance was calculated to be 1.70 +/- 0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32 +/- 0.58 microM, and that in the bone marrow plasma was 10.44 +/- 5.06 microM. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.

Pharmacologic studies of intra-hepatic artery chemotherapy with degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the pharmacokinetics of 4 drugs administered via the hepatic artery was studied in 5 patients with colon carcinoma metastatic to the liver. The 4 drugs were 99m-technetium diethylenetriamine pentaacetic acid (99mTc-DTPA), an agent which is not metabolized in the liver, and floxuridine, doxorubicin, and mitomycin, agents which undergo hepatic metabolism to varying extents. DSM transiently decreased arterial blood flow to normal liver an average of 64% and to hepatic tumor an average of 78%. DSM increased tumor exposure to DTPA by a mean of 1.71-fold, and increased hepatic exposure by 1.46-fold, but did not affect total plasma exposure. In contrast, DSM did reduce total plasma exposure to floxuridine by a mean of 34%, and to mitomycin by 20%. No information was available on the effect of DSM on plasma doxorubicin levels which never exceeded the limits of detection. Variation in the injection rate of DSM did not appear to influence the relative advantages produced in tumor or plasma AUCs. The estimated increase in tumor exposure produced by DSM was 3.8-fold for floxuridine, and 3.0-fold for mitomycin. These results reflect the differences in extent of hepatic metabolism of these agents, and agree closely with predictions made from mathematical models. Although DSM improved the therapeutic index, the increase in tumor exposure was insufficient to produce significant tumor regression.

Peritoneal access for intracavitary chemotherapy.

Direct intraperitoneal instillation of many chemotherapeutic agents can markedly increase total peritoneal drug exposure and may be useful for the treatment of ovarian carcinoma and mesothelioma. The use of a totally implanted access system (Port-a-CathTM) reduces the risk of inadvertent bowel damage, and infection associated with repeated intraperitoneal instillation of drugs. In addition, patient acceptance is better in comparison to catheters that protrude through the skin. Catheter failure due to the formation of adhesions around the outside of the catheter remains a major problem.

High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity.

Recent published reports have suggested that cisplatin administered in high doses or in certain combination chemotherapy can cause serious neurotoxicity in a large percentage of patients treated. In several high-dose cisplatin-based intracavitary chemotherapy trials with the simultaneous intravenous administration of sodium thiosulfate, the incidence of clinically relevant neurotoxicity has been extremely low. In addition, several patients with serious preexisting cisplatin-induced neurologic dysfunction were treated without worsening of their clinical condition. It is suggested that thiosulfate might have been responsible for the low incidence of neurotoxicity in this patient population. Further experimental and clinical investigation of the potential of this agent to protect against cisplatin-induced neuropathy appears warranted.

High-dose cisplatin with sodium thiosulfate protection.

Nephrotoxicity frequently limits the dose of cisplatin to less than 120 mg/m2 per injection. Sodium thiosulfate is a neutralizing agent for cisplatin that protects against renal damage. To determine whether injection of thiosulfate would permit larger doses of cisplatin to be administered, a fixed 9.9-g/m2 dose of thiosulfate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulfate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225 mg/m2 before dose-limiting toxicities were encountered. Comparison of cisplatin pharmacokinetics in patients treated with 202.5 mg/m2 plus thiosulfate to those in patients treated with 100 mg/m2 without thiosulfate indicated that there were no changes in the elimination rate constant, volume of distribution, or total body clearance of cisplatin. The total drug exposure for the plasma was approximately twofold at the higher cisplatin dose. This study demonstrates that concurrent administration of thiosulfate permits at least a twofold increase in dose and total exposure to cisplatin.

Intracavitary cisplatin chemotherapy for mesothelioma.

A feasibility study of intracavitary cisplatin was conducted in eight patients with mesothelioma. Cisplatin, 90 mg/m2, was instilled weekly for 3 weeks, followed by a 3-week rest; thiosulfate was given iv to reduce nephrotoxicity. In 50 courses there was no chemical serositis; the major toxic effect was myelosuppression. One patient with measurable disease had a complete response; three others had objective responses.

Maintenance of peritoneal catheter function by the intraperitoneal administration of 32% dextran 70.

Thirty-two percent dextran 70 was administered to 53 patients receiving intraperitoneal (i.p.) chemotherapy in an attempt to better maintain catheter function. One hundred milliliters of 32% dextran 70 was administered i.p. at the time of catheter placement and at the completion of each course of chemotherapy (every 3 to 4 weeks). Analysis of the functional survival of the dextran treated catheters and 20 historical controls was performed. The cumulative probabilities of catheters maintaining bi-directional function in the dextran treated and control groups were 0.75 and 0.50 respectively. This difference was statistically significant at p = 0.051 by two-tailed Wilcoxon analysis. The difference between survival of dextran treated and control catheters increased if patients who received intraperitoneal doxorubicin were factored out (p = 0.035 by two-tailed Wilcoxon analysis). Plasma and peritoneal dextran levels were measured on 9 courses in 8 patients. Dextran was detectable in the peritoneal cavity up to 7 days after administration. The "apparent half-life" of dextran 70 in the peritoneal cavity was 36 hours. Plasma dextran concentrations increased for 2 days following i.p. administration and then decreased with an apparent half-life of 36 hours. One patient experienced chills and another had an anaphylactoid reaction following administration of the dextran. This study suggests that i.p. administration of 32% dextran 70 may be an effective means of minimizing peritoneal catheter failures.

Pilot study of intra-arterial floxuridine, mitomycin and doxorubicin in combination with degradable starch microspheres to treat primary and metastatic tumors of the liver.

Concurrent administration of degradable starch microspheres and cytostatic agents into the hepatic artery results in decreased systemic exposure and increased hepatic exposure to drug compared to intra-arterial administration of drug alone. Degradable starch microspheres 210 mg/m2 mixed with floxuridine 500 mg/m2, doxorubicin 40 gm/m2, and mitomycin 10 mg/m2 were administered through hepatic artery catheters to eleven patients with primary or metastatic cancer of the liver. Toxicity was acceptable and consisted of severe myelosuppression (5%), duodenal/gastric ulceration (9%), mild to moderate nausea and vomiting (17%) and alopecia (86%). There were no responses among the eleven patients; 7 of 7 patients with colo-rectal carcinoma had stable disease while on study. Minimal activity was observed in 7 patients with colo-rectal carcinoma. The use of degradable starch microspheres offers a new approach to the regional treatment of cancer and warrants further study.

Combination intraperitoneal chemotherapy with cisplatin, cytarabine, and doxorubicin for refractory ovarian carcinoma and other malignancies principally confined to the peritoneal cavity.

Thirty-one patients with refractory ovarian cancer and other malignancies principally confined to the abdominal cavity were treated with an intraperitoneal combination-chemotherapy regimen consisting of cisplatin (100 to 200 mg/m2), cytosine arabinoside (10(-4) to 10(-3) mol/L) and doxorubicin (2 to 18 mumol/L). Sodium thiosulfate was simultaneously administered intravenously to prevent cisplatin-induced nephrotoxicity. Eight of 26 evaluable patients demonstrated clinical response including seven of 17 (41%) with ovarian cancer refractory to frontline chemotherapy. Systemic toxicity was mild except for nausea and vomiting. Abdominal pain secondary to doxorubicin was the major complication of therapy. We conclude that combination intraperitoneal therapy with cisplatin, cytosine arabinoside, and doxorubicin can be safely administered with objective tumor responses observed in patients with ovarian cancer heavily pretreated and in individuals with other malignancies involving the peritoneal cavity. Doxorubicin-induced local pain limits the ability to administer multiple courses of this treatment regimen.

Totally implantable system for peritoneal access.

A totally implantable system for providing access to the peritoneal cavity was evaluated. Fifty-six Port-A-Cath (Pharmacia Nu Tech, Piscataway, NJ) peritoneal access systems were implanted in 54 cancer patients receiving intraperitoneal chemotherapy. The catheters are accessed by transcutaneous placement of a Huber point needle through a silicone septum at the top of the portal. A total of 32 patient years of experience are reported. The Port-A-Caths have been in place for a median of 22 weeks (range, one to 85). A total of 401 entries have been made for paracentesis, chemotherapy administration, antibiotic administration, peritoneal lavage for cytology, and catheter flushing. There have been six episodes of peritonitis (five Staphylococcus epidermidis, one S aureus) in three patients. There have been no mechanical failures of the Port-A-Caths. Loss of bidirectional flow through the catheter due to fibrin deposition about the catheter has been the major cause of catheter failure. Patient acceptance of the Port-A-Cath has been excellent.

Intraperitoneal chemotherapy with melphalan.

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Intraperitoneal cytosine arabinoside therapy in ovarian carcinoma.

Previous pharmacokinetic modeling has suggested that cytosine arabinoside (ara-C) may be an ideal agent for peritoneal administration in the treatment of intraabdominal neoplasms. In vitro drug sensitivity testing with clonogenic assays demonstrated sensitivity to the high concentrations of ara-C potentially achievable by intraperitoneal (IP) administration in five of nine patients with ovarian carcinoma. The kinetics of IP ara-C were then studied in three patients, and a 2 to 3 log concentration gradient was observed between the peritoneal compartment and plasma. Subsequently, the clinical efficacy of IP ara-C given for a five-day course every four weeks was evaluated in 10 patients with ovarian carcinoma who had failed systemic chemotherapy. Chemical peritonitis did not occur and systemic toxicity was minimal. Two patients were rendered free of disease and are alive without disease 14+ and 15+ months since therapy was discontinued. These results demonstrate that there is a very large pharmacologic advantage to the IP route of administration for ara-C, that ara-C is active against advanced ovarian carcinoma, and that the IP route of administration permits the cytokinetically rational use of very long durations of exposure for this cell-cycle phase-specific agent.

Clinical pharmacokinetics of intraarterial cisplatin in humans.

The pharmacokinetics of intraarterially administered cisplatin (DDP) were studied in three patients with large hepatic tumors, and one patient with a fibrous histiocytoma in the thigh, using an assay sensitive to only those forms of non-protein bound DDP capable of reacting with the nucleophilic ligand diethyldithiocarbamate. Each patient received continuous intravenous and intraarterial infusions at various dose rates, with and without concurrent infusion of the neutralizing agent sodium thiosulfate. Steady-state DDP concentrations were achieved within two hours, and the mean (+/- SEM) plasma clearance at infusion rates of 5-15 mg/m2 per hour was 345 +/- 45 mL/m2 per minute. Apparent plasma clearance did not vary significantly with route of infusion. Based on the plasma clearance, predicted values for the relative advantage of an intraarterial infusion (Rt) were less than two for hepatic infusion; observed values averaged 1.9 +/- 0.5 (+/- SEM). The infusion of thiosulfate did not significantly increase plasma clearance. The mean (+/- SEM) extraction ratio for hepatic infusions was 0.24 +/- 0.09, and for infusion of the peripheral soft tissue sarcoma it was 0.27 +/- 0.03. These data indicate that from the point of view of both the tumor and the systemic circulation there is only a limited pharmacologic advantage for intraarterial infusion of DDP into organs with plasma flows of greater than 350 mL/m2 per minute.

Phase I trial of cytarabine and hydroxyurea.

A combination of hydroxyurea (HU) and cytarabine (ara-C) can overcome ara-C resistance in vitro. To determine the pattern of toxicity of this combination, 22 patients with refractory leukemia and lymphoma were treated for 5 days with ara-C (100 mg/m2/day by constant infusion) and escalating doses of HU (0.375-1.77 g/m2 every 6 hours). Hematologic toxicity was severe even at the lowest HU dose level. Skin and mucosal toxic effects were frequent but not dose-limiting. No novel types of toxic effects were observed.